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Maurer C, Agostinetto E, Ameye L, Lambertini M, Martel S, Ponde N, Brandão M, Poggio F, Ferreira A, Schiff R, De Angelis C, Gelber RD, Dent S, Thomssen C, Piccart M, de Azambuja E. Association of statin use on survival outcomes of patients with early-stage HER2-positive breast cancer in the APHINITY trial. Breast Cancer Res Treat 2025; 212:57-69. [PMID: 40293644 PMCID: PMC12086115 DOI: 10.1007/s10549-025-07699-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2025] [Accepted: 04/04/2025] [Indexed: 04/30/2025]
Abstract
PURPOSE There is evidence that statins might improve the outcome of patients with breast cancer. The role of statins in patients with early HER2-positive breast cancer is unknown. Therefore, we explored the association between statin use and survival outcomes in early HER2-positive breast cancer patients in the phase III APHINITY trial (adjuvant pertuzumab/trastuzumab). METHODS All patients (intent-to-treat population, n = 4804) were included (6.2 years median follow-up database). The primary objective was to investigate the association of statin use on invasive disease-free survival (IDFS), distant relapse-free interval (DRFI), and overall survival (OS). Patients who received statins at baseline, or started statins within 1 year from randomization were considered statin users. Survival curves were estimated using the Kaplan-Meier method. We used a Cox proportional hazards model for multivariate analysis. RESULTS Overall, 423 (8.8%) patients were classified as statin users. They were older, more often postmenopausal, had a higher body mass index, more often diabetes, hypertension, coronary heart disease and hyperlipidemia, had smaller sized tumors, were treated more often with breast conserving surgery, and less often with anthracycline-containing regimens. Overall, 508 IDFS events (12.8% among statin users and 10.4% among non-statin users) and 272 deaths (8.5% and 5.4%, respectively) occurred. In multivariate analysis, statin use was not associated with IDFS (HR, 1.11; 95% CI, 0.80-1.52), DRFI (HR, 1.21; 95% CI, 0.81-1.81) nor OS (HR, 1.16; 95% CI, 0.78-1.73). CONCLUSION In APHINITY, statin use was not associated with improved survival outcomes. These results must be interpreted with caution due to the exploratory nature of the analysis and the associated limitations.
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Affiliation(s)
- Christian Maurer
- National Center for Tumor Diseases (NCT) Heidelberg, University Hospital and German Cancer Research Center Heidelberg, Im Neuenheimer Feld 460, 69120, Heidelberg, Germany.
- Department I of Internal Medicine, Center for Integrated Oncology Aachen Bonn Cologne Düsseldorf, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany.
| | - Elisa Agostinetto
- Université Libre de Bruxelles (ULB), Hôpital Universitaire de Bruxelles (HUB), Institut Jules Bordet, Rue Meylemeersch 90, 1070, Brussels, Belgium
| | - Lieveke Ameye
- Université Libre de Bruxelles (ULB), Hôpital Universitaire de Bruxelles (HUB), Institut Jules Bordet, Rue Meylemeersch 90, 1070, Brussels, Belgium
| | - Matteo Lambertini
- Department of Internal Medicine and Medical Specialties (DiMI), School of Medicine, University of Genova, Genoa, Italy
- Department of Medical Oncology, U.O. Clinical Di Oncologia Medica, IRCCS Ospedale Policlinico San Martino, Genoa, Italy
| | - Samuel Martel
- Specialised Medicine Department, CISSS Montérégie-Centre/Hôpital Charles-Le Moyne, Greenfield Park, Québec, Canada
- Université of Sherbrooke, Sherbrooke, Québec, Canada
| | - Noam Ponde
- Clinical Development Department, Daiichi Sankyo, Morristown, NJ, USA
| | - Mariana Brandão
- Université Libre de Bruxelles (ULB), Hôpital Universitaire de Bruxelles (HUB), Institut Jules Bordet, Rue Meylemeersch 90, 1070, Brussels, Belgium
| | - Francesca Poggio
- Department of Medical Oncology, U.O. Clinical Di Oncologia Medica, IRCCS Ospedale Policlinico San Martino, Genoa, Italy
| | - Arlindo Ferreira
- Católica Medical School, Universidade Católica Portuguesa, Lisbon, Portugal
| | - Rachel Schiff
- Lester and Sue Smith Breast Center, Departments of Medicine and of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, USA
| | - Carmine De Angelis
- Medical Oncology Unit, Department of Clinical Medicine and Surgery, University of Naples "Federico II", Naples, Italy
| | - Richard D Gelber
- Harvard Medical School, Harvard TH Chan School of Public Health, Dana-Farber Cancer Institute, Frontier Science Foundation, Boston, MA, USA
| | - Susan Dent
- Wilmot Cancer Institute, Department of Medicine, University of Rochester, Rochester, NY, USA
| | - Christoph Thomssen
- Department of Gynaecology, Martin-Luther-University Halle-Wittenberg, Halle (Saale), Germany
| | - Martine Piccart
- Université Libre de Bruxelles (ULB), Hôpital Universitaire de Bruxelles (HUB), Institut Jules Bordet, Rue Meylemeersch 90, 1070, Brussels, Belgium
| | - Evandro de Azambuja
- Université Libre de Bruxelles (ULB), Hôpital Universitaire de Bruxelles (HUB), Institut Jules Bordet, Rue Meylemeersch 90, 1070, Brussels, Belgium
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de Moraes FCA, de Souza Wagner PH, de Lara ICA, Silva BL, Silva ALS, de Oliveira Macena Lôbo A, de Carvalho LIA, Kreuz M, Magalhães MCF, Burbano RMR. Statins and prognosis of female breast cancer: a meta-analysis. Clin Transl Oncol 2025:10.1007/s12094-025-03935-9. [PMID: 40285811 DOI: 10.1007/s12094-025-03935-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2025] [Accepted: 04/10/2025] [Indexed: 04/29/2025]
Abstract
BACKGROUND Breast cancer (BC) incidence is estimated to achieve over 3-million new cases and one million deaths by 2040. Beyond its physical toll, breast cancer detrimentally affects quality of life, imposing emotional, social, and financial burdens on patients and their families. Statins, commonly prescribed for managing cardiovascular health, have garnered attention for their potential role in breast cancer management. Emerging evidence suggests that statins possess anti-proliferative properties, which could impact BC progression. Understanding the potential benefits of statin therapy in BC patients is crucial for optimizing treatment strategies and improving outcomes. METHODS Hazard ratio (HR) with 95% confidence intervals (CIs) were calculated to evaluate the outcomes. The DerSimonian and Laird random-effects model was used for all pooled analyses. Heterogeneity was assessed using the I2 statistic with corresponding 95% CIs, considering I2 > 25% as indicative of substantial heterogeneity. Statistical analyses were conducted in R (version 4.3.2) using the "meta" package, with a significance level set at P < 0.05. RESULTS A total of 31 studies and 344,936 patients were included, of whom 72,784 (21.1%) was in the statins group and 272,152 (78.9%) was in the non-statin users group. Statin therapy was associated with a significantly reduced risks of all-cause mortality (HR 0.8583; 95% CI 0.7980-0.9231; P < 0.001; I2 = 81.1%), of BCSM (HR 0.8183; 95% CI 0.7334-0.9132; P < 0.001; I2 = 84.4%), and of BC recurrence (HR 0.7911; 95% CI 0.6882-0.9095; P < 0.001; I2 = 48.6%). However, the analysis of DFS did not show a statistically significant difference between the groups (HR 0.8415; 95% CI 0.4220-1.6780; P = 0.624; I2 = 74.2%). CONCLUSION Our meta-analysis suggests that statin therapy may confer beneficial effects on clinical outcomes in female breast cancer patients, including reduced all-cause mortality, breast cancer-specific mortality, and recurrence. However, further research is warranted to confirm these findings and elucidate the mechanisms underlying these associations.
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Affiliation(s)
| | | | | | - Barbara Lins Silva
- Vancouver Island Health Authority, 1947 Cook St, Victoria, BC, V8 T 3P7, Canada
| | | | | | | | - Michele Kreuz
- Lutheran University of Brazil, Canoas, Rio Grande do Sul, 92425-900, Brazil
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Guo H, Malone KE, Heckbert SR, Li CI. Statin use and risks of breast cancer recurrence and mortality. Cancer 2024; 130:3106-3114. [PMID: 38709898 DOI: 10.1002/cncr.35362] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2024] [Revised: 04/05/2024] [Accepted: 04/23/2024] [Indexed: 05/08/2024]
Abstract
BACKGROUND Preclinical evidence suggests improved breast cancer survival associated with statin use, but findings from observational studies are conflicting and remain inconclusive. The objective of this study was to assess the association between statin use after cancer diagnosis and cancer outcomes among breast cancer patients. METHODS In this retrospective cohort study, 38,858 women aged ≥66 years who were diagnosed with localized and regional stage breast cancer from 2008 through 2017 were identified from the linked Surveillance, Epidemiology, and End Results Medicare database. Statin use was ascertained from Medicare Part D pharmacy claims data. Multivariable Cox proportional hazards models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for the association between post-diagnosis statin use and risks of breast cancer recurrence and breast cancer-specific mortality. RESULTS Over a median follow-up of 2.9 years for recurrence and 3.7 years for mortality, 1446 women experienced a recurrence, and 2215 died from breast cancer. The mean duration of post-diagnosis statin use was 2.2 years. Statin use post-diagnosis was not associated with recurrence risk (HR, 1.05; 95% CI, 0.91-1.21), but was associated with a reduced risk of cancer-specific mortality (HR, 0.85; 95% CI, 0.75-0.96). The reduction was more pronounced in women with hormone receptor-positive/human epidermal growth factor receptor 2-negative breast cancer (HR, 0.71; 95% CI, 0.57-0.88). CONCLUSIONS These findings suggest that post-diagnosis statin use is associated with improved cancer-specific survival in women with breast cancer and should be confirmed in randomized trials of statin therapy in breast cancer patients.
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Affiliation(s)
- Hanbing Guo
- Division of Public Health Sciences, Fred Hutchinson Cancer Center, Seattle, Washington, USA
- Department of Epidemiology, University of Washington, Seattle, Washington, USA
| | - Kathleen E Malone
- Division of Public Health Sciences, Fred Hutchinson Cancer Center, Seattle, Washington, USA
- Department of Epidemiology, University of Washington, Seattle, Washington, USA
| | - Susan R Heckbert
- Department of Epidemiology, University of Washington, Seattle, Washington, USA
| | - Christopher I Li
- Division of Public Health Sciences, Fred Hutchinson Cancer Center, Seattle, Washington, USA
- Department of Epidemiology, University of Washington, Seattle, Washington, USA
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Tanaka J, Kuwajima H, Yuki R, Nakayama Y. Simvastatin activates the spindle assembly checkpoint and causes abnormal cell division by modifying small GTPases. Cell Signal 2024; 119:111172. [PMID: 38604342 DOI: 10.1016/j.cellsig.2024.111172] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2023] [Revised: 04/06/2024] [Accepted: 04/08/2024] [Indexed: 04/13/2024]
Abstract
Simvastatin is an inhibitor of 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) reductase, which is a rate-limiting enzyme of the cholesterol synthesis pathway. It has been used clinically as a lipid-lowering agent to reduce low-density lipoprotein (LDL) cholesterol levels. In addition, antitumor activity has been demonstrated. Although simvastatin attenuates the prenylation of small GTPases, its effects on cell division in which small GTPases play an important role, have not been examined as a mechanism underlying its cytostatic effects. In this study, we determined its effect on cell division. Cell cycle synchronization experiments revealed a delay in mitotic progression in simvastatin-treated cells at concentrations lower than the IC50. Time-lapse imaging analysis indicated that the duration of mitosis, especially from mitotic entry to anaphase onset, was prolonged. In addition, simvastatin increased the number of cells exhibiting misoriented anaphase/telophase and bleb formation. Inhibition of the spindle assembly checkpoint (SAC) kinase Mps1 canceled the mitotic delay. Additionally, the number of cells exhibiting kinetochore localization of BubR1, an essential component of SAC, was increased, suggesting an involvement of SAC in the mitotic delay. Enhancement of F-actin formation and cell rounding at mitotic entry indicates that cortical actin dynamics were affected by simvastatin. The cholesterol removal agent methyl-β-cyclodextrin (MβCD) accelerated mitotic progression differently from simvastatin, suggesting that cholesterol loss from the plasma membrane is not involved in the mitotic delay. Of note, the small GTPase RhoA, which is a critical factor for cortical actin dynamics, exhibited upregulated expression. In addition, Rap1 was likely not geranylgeranylated. Our results demonstrate that simvastatin affects actin dynamics by modifying small GTPases, thereby activating the spindle assembly checkpoint and causing abnormal cell division.
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Affiliation(s)
- Junna Tanaka
- Laboratory of Biochemistry and Molecular Biology, Kyoto Pharmaceutical University, Kyoto 607-8414, Japan
| | - Hiroki Kuwajima
- Laboratory of Biochemistry and Molecular Biology, Kyoto Pharmaceutical University, Kyoto 607-8414, Japan
| | - Ryuzaburo Yuki
- Laboratory of Biochemistry and Molecular Biology, Kyoto Pharmaceutical University, Kyoto 607-8414, Japan
| | - Yuji Nakayama
- Laboratory of Biochemistry and Molecular Biology, Kyoto Pharmaceutical University, Kyoto 607-8414, Japan.
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Bucci T, Gue Y, Dobson R, Palmieri C, Pignatelli P, Lip GYH. Statin use is associated with a lower risk of all-cause death in patients with breast cancer treated with anthracycline containing regimens: a global federated health database analysis. Clin Exp Med 2024; 24:124. [PMID: 38865021 PMCID: PMC11168976 DOI: 10.1007/s10238-024-01395-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2023] [Accepted: 06/07/2024] [Indexed: 06/13/2024]
Abstract
Anthracyclines are associated with enhanced oxidative stress responsible for adverse events in patients with breast cancer. However, no study has investigated the potential anti-inflammatory role of statins in counteracting anthracycline toxicity. In this retrospective study utilizing a federated health network (TriNetX), patients with breast cancer (ICD code C50) treated with anthracyclines were categorized into two groups: statin users (for at least 6 months); and statin non-users. The primary outcome was the 5-year risk of all-cause death. Secondary outcomes were the risk of myocardial infarction, stroke, atrial fibrillation, ventricular arrhythmias, heart failure, and pulmonary embolism. Cox-regression analyses were used to produce hazard ratios (HRs) and 95% confidence intervals (CI) following 1:1 propensity score matching (PSM). We identified 3,701 statin users (68.8 ± 10.4 years) and 37,185 statin non-users (59.6 ± 12.8 years). After PSM, the 5-year risk of all-cause death was significantly lower in statin users (HR 0.82, 95% CI 0.74-0.91) compared to statins non-users. Analyzing the risk for secondary outcomes, only the risk of stroke was significantly increased in statin users (HR 1.27, 95% CI 1.01-1.61), while no associations were found for the other cardiovascular events. The risk of all-cause death in statin users was the lowest during the first year after the anthracycline's initiation. No significant difference was found between lipophilic and hydrophilic statins. In patients with breast cancer treated with anthracyclines, statin use is associated with a reduced risk of all-cause death. Prospective studies are needed to investigate the potential beneficial effect of statin initiation in cancer patients without other indications.
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Affiliation(s)
- Tommaso Bucci
- Liverpool Centre of Cardiovascular Science at University of Liverpool, Liverpool John Moores University and Liverpool Heart and Chest Hospital, Liverpool, UK.
- Department of Clinical Internal, Anesthesiologic and Cardiovascular Sciences, Sapienza University of Rome, Rome, Italy.
| | - Ying Gue
- Liverpool Centre of Cardiovascular Science at University of Liverpool, Liverpool John Moores University and Liverpool Heart and Chest Hospital, Liverpool, UK
| | - Rebecca Dobson
- Liverpool Centre of Cardiovascular Science at University of Liverpool, Liverpool John Moores University and Liverpool Heart and Chest Hospital, Liverpool, UK
| | - Carlo Palmieri
- Liverpool Centre of Cardiovascular Science at University of Liverpool, Liverpool John Moores University and Liverpool Heart and Chest Hospital, Liverpool, UK
- Department of Molecular and Clinical Cancer Medicine, Institute of Translational Medicine, University of Liverpool, Liverpool, UK
- The Clatterbridge Cancer Centre NHS Foundation Trust, Liverpool, UK
| | - Pasquale Pignatelli
- Department of Clinical Internal, Anesthesiologic and Cardiovascular Sciences, Sapienza University of Rome, Rome, Italy
| | - Gregory Y H Lip
- Liverpool Centre of Cardiovascular Science at University of Liverpool, Liverpool John Moores University and Liverpool Heart and Chest Hospital, Liverpool, UK.
- Department of Clinical Medicine, Danish Center for Health Services Research, Aalborg University, Aalborg, Denmark.
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Maged A, Mabrouk M, Nour El-Din HT, Osama L, Badr-Eldin SM, Mahmoud AA. PLGA and PDMS-based in situ forming implants loaded with rosuvastatin and copper-selenium nanoparticles: a promising dual-effect formulation with augmented antimicrobial and cytotoxic activity in breast cancer cells. Front Pharmacol 2024; 15:1397639. [PMID: 38895619 PMCID: PMC11183308 DOI: 10.3389/fphar.2024.1397639] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2024] [Accepted: 05/13/2024] [Indexed: 06/21/2024] Open
Abstract
Breast cancer is among the most prevalent tumors worldwide. In this study, in-situ forming implants (ISFIs) containing rosuvastatin calcium were prepared using three types of poly (D, L-lactic-co-glycolic acid) (PLGA), namely, PLGA 50/50 with ester terminal and PLGA 75/25 with ester or acid terminal. Additionally, polydimethylsiloxane (PDMS) was added in concentrations of 0, 10, 20, and 30% w/v to accelerate matrix formation. The prepared ISFIs were characterized for their rheological behaviors, rate of matrix formation, and in-vitro drug release. All the prepared formulations revealed a Newtonian flow with a matrix formation rate between 0.017 and 0.059 mm/min. Generally, increasing the concentration of PDMS increased the matrix formation rate. The prepared implants' release efficiency values ranged between 46.39 and 89.75%. The ISFI containing PLGA 50/50 with 30% PDMS was selected for further testing, as it has the highest matrix formation rate and a promising release efficiency value. Copper-selenium nanoparticles were prepared with two different particle sizes (560 and 383 nm for CS1 and CS2, respectively) and loaded into the selected formulation to enhance its anticancer activity. The unloaded and loaded implants with rosuvastatin and copper-selenium nanoparticles were evaluated for their antibacterial activity, against Gram-positive and negative microorganisms, and anticancer efficacy, against MCF-7 and MDA-MB-231 cell lines. The results confirmed the potency of rosuvastatin calcium against cancer cells and the synergistic effect when loaded with smaller particle sizes of copper-selenium nanoparticles. This formulation holds a considerable potential for efficient breast cancer therapy.
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Affiliation(s)
- Amr Maged
- Pharmaceutics and Pharmaceutical Technology Department, Faculty of Pharmacy, Future University in Egypt, New Cairo, Egypt
- Pharmaceutical Factory, Faculty of Pharmacy, Future University in Egypt, New Cairo, Egypt
| | - Mostafa Mabrouk
- Refractories, Ceramics and Building Materials Department, National Research Centre, Giza, Egypt
| | - Hanzada T. Nour El-Din
- Microbiology and Immunology Department, Faculty of Pharmacy, Cairo University, Cairo, Egypt
| | - Lamyaa Osama
- Refractories, Ceramics and Building Materials Department, National Research Centre, Giza, Egypt
| | - Shaimaa M. Badr-Eldin
- Pharmaceutics Department, Faculty of Pharmacy, King Abdulaziz University, Jeddah, Saudi Arabia
- Center of Excellence for Drug Research and Pharmaceutical Industries, King Abdulaziz University, Jeddah, Saudi Arabia
| | - Azza A. Mahmoud
- Pharmaceutics and Pharmaceutical Technology Department, Faculty of Pharmacy, Future University in Egypt, New Cairo, Egypt
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Erazo-Oliveras A, Muñoz-Vega M, Salinas ML, Wang X, Chapkin RS. Dysregulation of cellular membrane homeostasis as a crucial modulator of cancer risk. FEBS J 2024; 291:1299-1352. [PMID: 36282100 PMCID: PMC10126207 DOI: 10.1111/febs.16665] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2022] [Revised: 09/09/2022] [Accepted: 10/24/2022] [Indexed: 11/07/2022]
Abstract
Cellular membranes serve as an epicentre combining extracellular and cytosolic components with membranous effectors, which together support numerous fundamental cellular signalling pathways that mediate biological responses. To execute their functions, membrane proteins, lipids and carbohydrates arrange, in a highly coordinated manner, into well-defined assemblies displaying diverse biological and biophysical characteristics that modulate several signalling events. The loss of membrane homeostasis can trigger oncogenic signalling. More recently, it has been documented that select membrane active dietaries (MADs) can reshape biological membranes and subsequently decrease cancer risk. In this review, we emphasize the significance of membrane domain structure, organization and their signalling functionalities as well as how loss of membrane homeostasis can steer aberrant signalling. Moreover, we describe in detail the complexities associated with the examination of these membrane domains and their association with cancer. Finally, we summarize the current literature on MADs and their effects on cellular membranes, including various mechanisms of dietary chemoprevention/interception and the functional links between nutritional bioactives, membrane homeostasis and cancer biology.
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Affiliation(s)
- Alfredo Erazo-Oliveras
- Program in Integrative Nutrition and Complex Diseases; Texas A&M University; College Station, Texas, 77843; USA
- Department of Nutrition; Texas A&M University; College Station, Texas, 77843; USA
| | - Mónica Muñoz-Vega
- Program in Integrative Nutrition and Complex Diseases; Texas A&M University; College Station, Texas, 77843; USA
- Department of Nutrition; Texas A&M University; College Station, Texas, 77843; USA
| | - Michael L. Salinas
- Program in Integrative Nutrition and Complex Diseases; Texas A&M University; College Station, Texas, 77843; USA
- Department of Nutrition; Texas A&M University; College Station, Texas, 77843; USA
| | - Xiaoli Wang
- Program in Integrative Nutrition and Complex Diseases; Texas A&M University; College Station, Texas, 77843; USA
- Department of Nutrition; Texas A&M University; College Station, Texas, 77843; USA
| | - Robert S. Chapkin
- Program in Integrative Nutrition and Complex Diseases; Texas A&M University; College Station, Texas, 77843; USA
- Department of Nutrition; Texas A&M University; College Station, Texas, 77843; USA
- Center for Environmental Health Research; Texas A&M University; College Station, Texas, 77843; USA
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Alizadehasl A, Alavi MS, Boudagh S, Alavi MS, Mohebi S, Aliabadi L, Akbarian M, Ahmadi P, Mannarino MR, Sahebkar A. Lipid-lowering drugs and cancer: an updated perspective. Pharmacol Rep 2024; 76:1-24. [PMID: 38015371 DOI: 10.1007/s43440-023-00553-6] [Citation(s) in RCA: 5] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2023] [Revised: 10/27/2023] [Accepted: 10/27/2023] [Indexed: 11/29/2023]
Abstract
Statins and non-statin medications used for the management of dyslipidemia have been shown to possess antitumor properties. Since the use of these drugs has steadily increased over the past decades, more knowledge is required about their relationship with cancer. Lipid-lowering agents are heterogeneous compounds; therefore, it remains to be revealed whether anticancer potential is a class effect or related to them all. Here, we reviewed the literature on the influence of lipid-lowering medications on various types of cancer during development or metastasis. We also elaborated on the underlying mechanisms associated with the anticancer effects of antihyperlipidemic agents by linking the reported in vivo and in vitro studies.
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Affiliation(s)
- Azin Alizadehasl
- Cardio-Oncology Research Center, Rajaie Cardiovascular Medical and Research Center, Iran University of Medical Sciences, Tehran, Iran
- Echocardiography Research CenterRajaie Cardiovascular Medical and Research Center, Iran University of Medical Sciences, Tehran, Iran
| | - Maryam Sadat Alavi
- Echocardiography Research CenterRajaie Cardiovascular Medical and Research Center, Iran University of Medical Sciences, Tehran, Iran
| | - Shabnam Boudagh
- Echocardiography Research CenterRajaie Cardiovascular Medical and Research Center, Iran University of Medical Sciences, Tehran, Iran
| | - Mohaddeseh Sadat Alavi
- Pharmacological Research Center of Medicinal Plants, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Somaye Mohebi
- Echocardiography Research CenterRajaie Cardiovascular Medical and Research Center, Iran University of Medical Sciences, Tehran, Iran
| | - Leila Aliabadi
- Echocardiography Research CenterRajaie Cardiovascular Medical and Research Center, Iran University of Medical Sciences, Tehran, Iran
| | - Mahsa Akbarian
- Echocardiography Research CenterRajaie Cardiovascular Medical and Research Center, Iran University of Medical Sciences, Tehran, Iran
| | - Parisa Ahmadi
- Echocardiography Research CenterRajaie Cardiovascular Medical and Research Center, Iran University of Medical Sciences, Tehran, Iran
| | | | - Amirhossein Sahebkar
- Biotechnology Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran.
- Applied Biomedical Research Center, Mashhad University of Medical Sciences, Mashhad, Iran.
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9
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Xu WH, Zhang T, Zhou Y, Mao Y. Fluvastatin prevents lung metastasis in triple-negative breast cancer by triggering autophagy via the RhoB/PI3K/mTOR pathway. Exp Cell Res 2024; 435:113893. [PMID: 38123008 DOI: 10.1016/j.yexcr.2023.113893] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2023] [Revised: 12/11/2023] [Accepted: 12/14/2023] [Indexed: 12/23/2023]
Abstract
Triple-negative breast cancer is more common among younger than older women and is associated with the poorest survival outcomes of all breast cancer types. Fluvastatin inhibits tumour progression and induces the autophagy of breast cancer cells; however, the role of autophagy in fluvastatin-induced inhibition of breast cancer metastasis is unknown. Therefore, this study aimed to determine this mechanism. The effect of fluvastatin on human hormone receptor-negative breast cancer cells was evaluated in vitro via migration and wound healing assays, western blotting, and morphological measurements, as well as in vivo using a mouse xenograft model. Chloroquine, a prophylactic medication used to prevent malaria in humans was used as an autophagy inhibitor. We found that fluvastatin administration effectively prevented the migration/invasion of triple-negative breast cancer cells, an effect that was largely dependent on the induction of autophagy. Administration of the autophagy inhibitor chloroquine prevented the fluvastatin-induced suppression of lung metastasis in the nude mouse model. Furthermore, fluvastatin increased Ras homolog family member B (RhoB) expression, and the autophagy and anti-metastatic activity induced by fluvastatin were predominantly dependent on the regulation of RhoB through the protein kinase B-mammalian target of rapamycin (Akt-mTOR) signaling pathway. These results suggest that fluvastatin inhibits the metastasis of triple-negative breast cancer cells by modulating autophagy via the up regulation of RhoB through the AKT-mTOR signaling pathway. Fluvastatin may be a promising therapeutic option for patients with triple-negative breast cancer.
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Affiliation(s)
- Wen-Huan Xu
- Department of Medical Oncology, Affiliated Hospital of Jiangnan University, Hefeng road 1000, Wuxi, 214062, China
| | - Ting Zhang
- Institute of Cancer, Affiliated Hospital of Jiangnan University, Wuxi, Hefeng road 1000, 214062, China
| | - Yunhai Zhou
- Department of General Surgery, Wuxi No.2 People's Hospital, Nanjing Medical University, Zhongshan road 68, Wuxi, 214000, China
| | - Yong Mao
- Department of Medical Oncology, Affiliated Hospital of Jiangnan University, Hefeng road 1000, Wuxi, 214062, China.
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Kumar U. Somatostatin and Somatostatin Receptors in Tumour Biology. Int J Mol Sci 2023; 25:436. [PMID: 38203605 PMCID: PMC10779198 DOI: 10.3390/ijms25010436] [Citation(s) in RCA: 17] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2023] [Revised: 12/24/2023] [Accepted: 12/25/2023] [Indexed: 01/12/2024] Open
Abstract
Somatostatin (SST), a growth hormone inhibitory peptide, is expressed in endocrine and non-endocrine tissues, immune cells and the central nervous system (CNS). Post-release from secretory or immune cells, the first most appreciated role that SST exhibits is the antiproliferative effect in target tissue that served as a potential therapeutic intervention in various tumours of different origins. The SST-mediated in vivo and/or in vitro antiproliferative effect in the tumour is considered direct via activation of five different somatostatin receptor subtypes (SSTR1-5), which are well expressed in most tumours and often more than one receptor in a single cell. Second, the indirect effect is associated with the regulation of growth factors. SSTR subtypes are crucial in tumour diagnosis and prognosis. In this review, with the recent development of new SST analogues and receptor-specific agonists with emerging functional consequences of signaling pathways are promising therapeutic avenues in tumours of different origins that are discussed.
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Affiliation(s)
- Ujendra Kumar
- Faculty of Pharmaceutical Sciences, The University of British Columbia, Vancouver, BC V6T 1Z3, Canada
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11
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Jia X, Lu Y, Xu Z, Mu Q. Impact of statin use on breast cancer recurrence and mortality before and after diagnosis: a systematic review and meta-analysis. Front Oncol 2023; 13:1256747. [PMID: 38164196 PMCID: PMC10757972 DOI: 10.3389/fonc.2023.1256747] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2023] [Accepted: 11/23/2023] [Indexed: 01/03/2024] Open
Abstract
Objective Breast cancer is one of the most common causes of death among women. Statins, typically used for cholesterol management, have been hypothesized to reduce recurrence and mortality rates in breast cancer. However, this association remains a subject of debate. This study evaluates the potential impact of statins on breast cancer recurrence and mortality. Methods A comprehensive search was conducted in the PubMed, EMBASE, and Cochrane databases for articles published up to June 2023. These articles examined the effect of statins on breast cancer recurrence and mortality both before and after diagnosis. The analysis was performed using random-effects models, calculating pooled hazard ratios (HR) and their 95% confidence intervals (CI). Results A total of 31 cohort studies, involving 261,834 female breast cancer patients, were included in this analysis. It was found that statin use prior to diagnosis was associated with a decrease in overall mortality (HR, 0.8; 95% CI, 0.69-0.93; I2 = 77.6%; P = 0.001) and breast cancer-specific mortality (HR, 0.76; 95% CI, 0.67-0.87; I2 = 72.7%; P = 0.005). Additionally, statin use after diagnosis was observed to reduce the recurrence of breast cancer (HR, 0.71; 95% CI, 0.61-0.82; I2 = 60%; P = 0.003), overall mortality (HR, 0.81; 95% CI, 0.70-0.92; I2 = 80.7%; P < 0.001), and breast cancer-specific mortality (HR, 0.76; 95% CI, 0.67-0.86; I2 = 74.5%; P < 0.001). Conclusions The findings of this study indicate that statin usage, both before and after breast cancer diagnosis, may be associated with reduced risks of overall and breast cancer-specific mortality, as well as lower recurrence rates.
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Affiliation(s)
- Xiaolin Jia
- Department of Infectious Diseases, The Third People’s Hospital of Longgang Shenzhen, Shenzhen, China
| | - Ye Lu
- Department of Breast Surgical Oncology, National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Zili Xu
- Clinical Medicine School of Zhengzhou University, Zhengzhou, China
| | - Qingqing Mu
- Clinical Medicine School of Zhengzhou University, Zhengzhou, China
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12
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Jaiswal V, Agrawal V, Ang SP, Saleeb M, Ishak A, Hameed M, Rajak K, Kalra K, Jaiswal A. Post-diagnostic statin use and its association with cancer recurrence and mortality in breast cancer patients: a systematic review and meta-analysis. EUROPEAN HEART JOURNAL. CARDIOVASCULAR PHARMACOTHERAPY 2023; 9:731-740. [PMID: 37562940 DOI: 10.1093/ehjcvp/pvad057] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/06/2023] [Revised: 06/27/2023] [Accepted: 08/05/2023] [Indexed: 08/12/2023]
Abstract
BACKGROUND Statins are widely acknowledged for their application in patients with hypercholesterolemia to reduce cardiovascular morbidity and mortality. More recently, their potential to exert pleiotropic effects, particularly in impeding the proliferation of neoplastic cells, has attracted considerable attention. Prior studies have demonstrated that statins may mitigate cancer progression and micrometastasis. However, the benefits of statins in breast cancer have been inconclusive. OBJECTIVE The aim of this meta-analysis was to evaluate the impact of statin use following a breast cancer diagnosis on breast cancer recurrence and mortality. METHODS We performed a systematic literature search using PubMed, Embase, and Scopus for relevant articles from inception until 30th May 2023. Hazard ratios (HR) were pooled using a random-effect model. The primary outcome of interest was the risk of breast cancer recurrence. The secondary outcomes included breast cancer-specific mortality and all-cause mortality. RESULTS A total of 15 studies with 156 448 patients were included in the final analysis. The mean age of patients between statin users and non-users was 64.59 and 59.15 years, respectively. Statin use was associated with a reduction in the recurrence of breast cancer [HR 0.76, 95% confidence interval (CI): 0.67-0.87] compared with non-statin users. This trend was similar among lipophilic statin users (HR 0.73, 95% CI: 0.63-0.85) but not for hydrophilic statin users (HR 1.17, 95% CI: 0.82-1.68). Furthermore, statin users exhibited a lower risk of breast cancer mortality (HR 0.80, 95% CI: 0.66-0.96) but all-cause mortality (HR 0.82, 95% CI: 0.66-1.02) was comparable among both groups of patients. Conversely, lipophilic statins demonstrated a reduction in both all-cause mortality (HR 0.84, 95% CI: 0.75-0.93) and breast cancer mortality (HR 0.85, 95% CI: 0.74-0.99) compared to non-statin users. CONCLUSION Among patients with breast cancer, statin use post-diagnosis decreases the risk of breast cancer recurrence and breast cancer mortality. Furthermore, lipophilic statins exhibit an additional advantage of reduction in all-cause mortality.PROSPERO registration: CRD42022362011.
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Affiliation(s)
- Vikash Jaiswal
- Department of Cardiovascular Research, Larkin Community Hospital, South Miami, FL, 33143, USA
- JCCR Cardiology Research, Varanasi, 221005, India
| | - Vibhor Agrawal
- Department of Medicine, King George's Medical University, Lucknow, 226003, India
| | - Song Peng Ang
- Department of Internal Medicine, Rutgers Health/Community Medical Center, NJ 08755, USA
| | - Marina Saleeb
- Public Health Institute, Faculty of Health, Liverpool John Moores University, Liverpool L2 2QP, UK
| | - Angela Ishak
- Department of Internal Medicine, Henry Ford Hospital, Detroit, 48202, USA
| | - Maha Hameed
- Department of Internal Medicine, Florida State University/Sarasota Memorial Hospital, Sarasota, FL 34239, USA
| | - Kripa Rajak
- Department of Internal Medicine, UPMC, Harrisburg, PA 17101, USA
| | - Kriti Kalra
- Department of Cardiology, MedStar Washington Hospital Center, WD 20010, USA
| | - Akash Jaiswal
- Department of Geriatric Medicine, All India Institute of Medical Science, New Delhi, 110608, India
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13
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Murto MO, Simolin N, Arponen O, Siltari A, Artama M, Visvanathan K, Jukkola A, Murtola TJ. Statin Use, Cholesterol Level, and Mortality Among Females With Breast Cancer. JAMA Netw Open 2023; 6:e2343861. [PMID: 37976058 PMCID: PMC10656638 DOI: 10.1001/jamanetworkopen.2023.43861] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/10/2023] [Accepted: 10/05/2023] [Indexed: 11/19/2023] Open
Abstract
Importance Several studies have reported an association between the use of statins and breast cancer (BC) mortality. However, most of these studies did not take into account the underlying cholesterol level. Objective To investigate the association between serum cholesterol, statin use, and BC mortality. Design, Setting, and Participants This cohort study included females with invasive BC that was newly diagnosed between January 1, 1995, and December 31, 2013, in Finland. The cohort had available hormone receptor data and at least 1 cholesterol measurement. All data were obtained from Finnish national registries. Statistical analyses were performed from January to May 2022. Exposure Use of statins; statin dose; and serum cholesterol, low-density lipoprotein, high-density lipoprotein, and triglyceride levels measured separately before and after BC diagnosis. Main Outcomes and Measures Breast cancer mortality and overall mortality between date of BC diagnosis and December 31, 2015. Results A total of 13 378 female patients with BC (median [IQR] age, 62 [54-69] years) participated in the study. The median (IQR) follow-up was 4.5 (2.4-9.8) years after BC diagnosis, during which 16.4% of patients died and 7.0% died of BC. Prediagnostic statin use was a risk factor for BC death even after adjustment for total cholesterol level (hazard ratio [HR], 1.22; 95% CI, 1.02-1.46; P = .03). Reduced risk for BC death was seen for postdiagnostic statin use (HR, 0.85; 95% CI, 0.73-1.00; P = .05). The risk reduction was robust in participants whose cholesterol level decreased after starting statins (HR, 0.49; 95% CI, 0.32-0.75; P = .001) but was nonsignificant if cholesterol level did not subsequently decrease (HR, 0.69; 95% CI, 0.34-1.40; P = .30). Reduced BC mortality among statin users was also observed in females with estrogen receptor-positive tumors (HR, 0.82; 95% CI, 0.68-0.99; P = .03). Overall mortality was lower among statin users vs nonusers when adjusted for serum cholesterol level (HR, 0.80; 95% CI, 0.72-0.88; P < .001). Conclusions and Relevance Results of this cohort study showed that postdiagnostic use of statins was associated with reduced BC mortality compared with nonuse, and the risk was associated with subsequent change in serum cholesterol level. This finding suggests that cholesterol-lowering interventions with statins may be beneficial for patients with BC.
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Affiliation(s)
- Mika O. Murto
- Department of General Surgery, Tays Cancer Centre, Tampere, Finland
| | - Niklas Simolin
- Faculty of Medicine and Health Technology, University of Tampere, Tampere, Finland
| | - Otso Arponen
- Faculty of Medicine and Health Technology, University of Tampere, Tampere, Finland
- Department of Radiology, Tampere University Hospital, Tampere, Finland
| | - Aino Siltari
- Faculty of Medicine and Health Technology, University of Tampere, Tampere, Finland
- Department of Pharmacology, Faculty of Medicine, University of Helsinki, Helsinki, Finland
| | - Miia Artama
- Department of Health Protection, Finnish Institute for Health and Welfare, Tampere, Finland
| | - Kala Visvanathan
- Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland
- Department of Oncology, Johns Hopkins School of Medicine, Baltimore, Maryland
| | - Arja Jukkola
- Faculty of Medicine and Health Technology, University of Tampere, Tampere, Finland
- Department of Oncology, Tampere University Hospital, Tampere University, Tays Cancer Centre, Tampere, Finland
| | - Teemu J. Murtola
- Faculty of Medicine and Health Technology, University of Tampere, Tampere, Finland
- Department of Oncology, Tampere University Hospital, Tampere University, Tays Cancer Centre, Tampere, Finland
- Department of Urology, Tays Cancer Centre, Tampere, Finland
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14
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Löfling LL, Støer NC, Andreassen BK, Ursin G, Botteri E. Low-dose aspirin, statins, and metformin and survival in patients with breast cancers: a Norwegian population-based cohort study. Breast Cancer Res 2023; 25:101. [PMID: 37649039 PMCID: PMC10466817 DOI: 10.1186/s13058-023-01697-2] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2023] [Accepted: 08/14/2023] [Indexed: 09/01/2023] Open
Abstract
BACKGROUND Previous studies assessed the prognostic effect of aspirin, statins, and metformin in breast cancer (BC) patients, with inconclusive results. METHODS We performed a nationwide population-based cohort study to evaluate if post-diagnostic use of low-dose aspirin, statins, and metformin was associated with BC-specific survival. Women aged ≥ 50 years and diagnosed with BC in 2004-2017, who survived ≥ 12 months after diagnosis (follow-up started 12 months after diagnosis), were identified in the Cancer Registry of Norway. The Norwegian Prescription Database provided information on prescriptions. Multivariable Cox proportional hazard models were used to estimate hazard ratios (HR) and 95% confidence intervals (CI) for the association between post-diagnostic use and BC-specific survival, overall and by oestrogen receptor (ER) status. RESULTS A total of 26,190 patients were included. Of these, 5324 (20%), 7591 (29%), and 1495 (6%) were post-diagnostic users of low-dose aspirin, statins, and metformin, respectively. The median follow-up was 6.1 years, and 2169 (8%) patients died from BC. HRs for use, compared to no use, were estimated at 0.96 (95% CI 0.85-1.08) for low-dose aspirin (ER+: HR = 0.97, 95% CI 0.83-1.13; ER-: HR = 0.97, 95% CI 0.73-1.29, p value for interaction = 0.562), 0.84 (95% CI 0.75-0.94) for statins (ER+: HR = 0.95, 95% CI 0.82-1.09; ER-: HR = 0.77, 95% CI 0.60-1.00, p value for interaction = 0.259), and 0.70 (95% CI 0.51-0.96) for metformin (compared to use of non-metformin antidiabetics) (ER+: HR = 0.67, 95% CI 0.45-1.01; ER-: HR = 1.62, 95% CI 0.72-3.62, p value for interaction = 0.077). CONCLUSION We found evidence supporting an association between post-diagnostic use of statins and metformin and survival, in patients with BC. Our findings indicate potential differences according to ER status.
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Affiliation(s)
- L Lukas Löfling
- Department of Research, Cancer Registry of Norway, Postboks 5313 Majorstuen, 0304, Oslo, Norway
| | - Nathalie C Støer
- Department of Research, Cancer Registry of Norway, Postboks 5313 Majorstuen, 0304, Oslo, Norway
| | | | - Giske Ursin
- Cancer Registry of Norway, Oslo, Norway
- Department of Nutrition, Institute of Basic Medical Sciences, University of Oslo, Oslo, Norway
- Department of Preventive Medicine, University of Southern California, Los Angeles, USA
| | - Edoardo Botteri
- Department of Research, Cancer Registry of Norway, Postboks 5313 Majorstuen, 0304, Oslo, Norway.
- Section for Colorectal Cancer Screening, Cancer Registry of Norway, Oslo, Norway.
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15
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Post-diagnostic statin use and breast cancer-specific mortality: a population-based cohort study. Breast Cancer Res Treat 2023; 199:195-206. [PMID: 36930345 PMCID: PMC10147735 DOI: 10.1007/s10549-022-06815-w] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2022] [Accepted: 11/09/2022] [Indexed: 03/18/2023]
Abstract
PURPOSE Statins are the most widely prescribed cholesterol lowering medications and have been associated with both improved and unchanged breast cancer outcomes in previous studies. This study examines the association between the post-diagnostic use of statins and breast cancer outcomes (death and recurrence) in a large, representative sample of New Zealand (NZ) women with breast cancer. METHODS Women diagnosed with a first primary breast cancer between 2007 and 2016 were identified from four population-based regional NZ breast cancer registries and linked to national pharmaceutical data, hospital discharges, and death records. Cox proportional hazard models were used to estimate the hazard of breast cancer-specific death (BCD) associated with any post-diagnostic statin use. RESULTS Of the 14,976 women included in analyses, 27% used a statin after diagnosis and the median follow up time was 4.51 years. Statin use (vs non-use) was associated with a statistically significant decreased risk of BCD (adjusted hazard ratio: 0.74; 0.63-0.86). The association was attenuated when considering a subgroup of 'new' statin users (HR: 0.91; 0.69-1.19), however other analyses revealed that the protective effect of statins was more pronounced in estrogen receptor positive patients (HR: 0.77; 0.63-0.94), postmenopausal women (HR: 0.74; 0.63-0.88), and in women with advanced stage disease (HR: 0.65; 0.49-0.84). CONCLUSION In this study, statin use was associated with a statistically significant decreased risk of breast cancer death, with subgroup analyses revealing a more protective effect in ER+ patients, postmenopausal women, and in women with advanced stage disease. Further research is warranted to determine if these associations are replicated in other clinical settings.
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16
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Takada K, Kashiwagi S, Iimori N, Kouhashi R, Yabumoto A, Goto W, Asano Y, Tauchi Y, Morisaki T, Ogisawa K, Shibutani M, Tanaka H, Maeda K. Impact of oral statin therapy on clinical outcomes in patients with cT1 breast cancer. BMC Cancer 2023; 23:224. [PMID: 36894884 PMCID: PMC9999569 DOI: 10.1186/s12885-023-10631-w] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2022] [Accepted: 02/09/2023] [Indexed: 03/11/2023] Open
Abstract
PURPOSE A previous meta-analysis examining the relationship between statin use and breast cancer reported that the inhibitory effect of statins on breast cancer may be more pronounced in early-stage cases. In this study, we aimed to investigate the effects of hyperlipidemia treatment at the time of breast cancer diagnosis and to examine its correlation with metastasis to axillary lymph nodes among patients with so-called cT1 breast cancer whose primary lesion was 2 cm or less and was pathologically evaluated by sentinel lymph node biopsy or axillary lymph node dissection. We also investigated the effects of hyperlipidemic drugs on the prognosis of patients with early-stage breast cancer. METHODS After excluding cases that did not meet the criteria, we analyzed data from 719 patients who were diagnosed with breast cancer, with a primary lesion of 2 cm or less identified by preoperative imaging, and who underwent surgery without preoperative chemotherapy. RESULTS Regarding hyperlipidemia drugs, no correlation was found between statin use and lymph node metastasis (p = 0.226), although a correlation was found between lipophilic statin use and lymph node metastasis (p = 0.042). Also, the disease-free survival periods were prolonged following treatment of hyperlipidemia (p = 0.047, hazard ratio: 0.399) and statin administration (p = 0.028, hazard ratio: 0.328). CONCLUSION In cT1 breast cancer, the results suggest that oral statin therapy may contribute to favorable outcomes.
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Affiliation(s)
- Koji Takada
- Department of Breast Surgical Oncology, Osaka Metropolitan University Graduate School of Medicine, 1-4-3 Asahi-machi, Abeno-ku, Osaka, 545-8585, Japan
| | - Shinichiro Kashiwagi
- Department of Breast Surgical Oncology, Osaka Metropolitan University Graduate School of Medicine, 1-4-3 Asahi-machi, Abeno-ku, Osaka, 545-8585, Japan.
| | - Nozomi Iimori
- Department of Breast Surgical Oncology, Osaka Metropolitan University Graduate School of Medicine, 1-4-3 Asahi-machi, Abeno-ku, Osaka, 545-8585, Japan
| | - Rika Kouhashi
- Department of Breast Surgical Oncology, Osaka Metropolitan University Graduate School of Medicine, 1-4-3 Asahi-machi, Abeno-ku, Osaka, 545-8585, Japan
| | - Akimichi Yabumoto
- Department of Breast Surgical Oncology, Osaka Metropolitan University Graduate School of Medicine, 1-4-3 Asahi-machi, Abeno-ku, Osaka, 545-8585, Japan
| | - Wataru Goto
- Department of Breast Surgical Oncology, Osaka Metropolitan University Graduate School of Medicine, 1-4-3 Asahi-machi, Abeno-ku, Osaka, 545-8585, Japan
| | - Yuka Asano
- Department of Breast Surgical Oncology, Osaka Metropolitan University Graduate School of Medicine, 1-4-3 Asahi-machi, Abeno-ku, Osaka, 545-8585, Japan
| | - Yukie Tauchi
- Department of Breast Surgical Oncology, Osaka Metropolitan University Graduate School of Medicine, 1-4-3 Asahi-machi, Abeno-ku, Osaka, 545-8585, Japan
| | - Tamami Morisaki
- Department of Breast Surgical Oncology, Osaka Metropolitan University Graduate School of Medicine, 1-4-3 Asahi-machi, Abeno-ku, Osaka, 545-8585, Japan
| | - Kana Ogisawa
- Department of Breast Surgical Oncology, Osaka Metropolitan University Graduate School of Medicine, 1-4-3 Asahi-machi, Abeno-ku, Osaka, 545-8585, Japan
| | - Masatsune Shibutani
- Department of Gastroenterological Surgery, Osaka Metropolitan University Graduate School of Medicine, 1-4-3 Asahi-machi, Abeno-ku, Osaka, 545-8585, Japan
| | - Hiroaki Tanaka
- Department of Gastroenterological Surgery, Osaka Metropolitan University Graduate School of Medicine, 1-4-3 Asahi-machi, Abeno-ku, Osaka, 545-8585, Japan
| | - Kiyoshi Maeda
- Department of Gastroenterological Surgery, Osaka Metropolitan University Graduate School of Medicine, 1-4-3 Asahi-machi, Abeno-ku, Osaka, 545-8585, Japan
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17
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Zipinotti Dos Santos D, Santos Guimaraes ID, Hakeem-Sanni MF, Cochran BJ, Rye KA, Grewal T, Hoy AJ, Rangel LBA. Atorvastatin improves cisplatin sensitivity through modulation of cholesteryl ester homeostasis in breast cancer cells. Discov Oncol 2022; 13:135. [PMID: 36481936 PMCID: PMC9732177 DOI: 10.1007/s12672-022-00598-8] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/28/2022] [Accepted: 12/01/2022] [Indexed: 12/13/2022] Open
Abstract
BACKGROUND Acquired treatment resistance is a significant problem in breast cancer management, and alterations in lipid metabolism have been proposed to contribute to the development of drug resistance as well as other aspects of tumor progression. The present study aimed to identify the role of cholesterol metabolism in MCF-7 and MDA-MB-231 breast cancer cell response to cisplatin (CDDP) treatment in the acute setting and in a model of CDDP resistance. METHODS MCF-7 (luminal A), MDA-MB-231 (triple-negative) and CDDP-resistant MDA-MB-231 (MDACR) cell lines were grown in the presence or absence of CDDP in combination with atorvastatin (ATV), lipid depletion or low-density lipoprotein loading and were analyzed by a variety of biochemical and radiometric techniques. RESULTS Co-administration of CDDP and ATV strongly reduced cell proliferation and viability to a greater extent than CDDP alone, especially in MDA-MB-231 cells. These findings were associated with reduced cholesteryl ester synthesis and storage in MDA-MB-231 cells. In MDACR cells, acetyl-CoA acetyltransferase 1 (ACAT-1) was upregulated compared to naïve MDA-MB-231 cells and ATV treatment restored CDDP sensitivity, suggesting that aberrant ACAT-1 expression and associated changes in cholesterol metabolism contribute to CDDP resistance in MDA-MB-231 cells. CONCLUSION These findings indicate that the elevated susceptibility of MDA-MB-231 cells to co-administration of CDDP and ATV, is associated with an increased reliance on cholesteryl ester availability. Our data from these cell culture-based studies identifies altered cholesterol homeostasis as an adaptive response to CDDP treatment that contributes to aggressiveness and chemotherapy resistance.
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Affiliation(s)
- Diandra Zipinotti Dos Santos
- Biotechnology Program/RENORBIO, Health Sciences Center, Universidade Federal do Espírito Santo, Vitoria, ES, Brazil
| | | | - Mariam F Hakeem-Sanni
- School of Medical Sciences, Charles Perkins Centre, Faculty of Medicine and Health, The University of Sydney, Sydney, NSW, Australia
| | - Blake J Cochran
- School of Medical Sciences, Faculty of Medicine, UNSW, Sydney, NSW, Australia
| | - Kerry-Anne Rye
- School of Medical Sciences, Faculty of Medicine, UNSW, Sydney, NSW, Australia
| | - Thomas Grewal
- School of Pharmacy, Faculty of Medicine and Health, The University of Sydney, Sydney, NSW, Australia
| | - Andrew J Hoy
- School of Medical Sciences, Charles Perkins Centre, Faculty of Medicine and Health, The University of Sydney, Sydney, NSW, Australia.
| | - Leticia B A Rangel
- Biotechnology Program/RENORBIO, Health Sciences Center, Universidade Federal do Espírito Santo, Vitoria, ES, Brazil.
- Biochemistry Program, Health Sciences Center, Universidade Federal do Espirito Santo, Vitoria, ES, Brazil.
- Department of Pharmaceutical Sciences, Universidade Federal do Espírito Santo, Vitória, Brazil.
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18
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Shaghaghi Z, Alvandi M, Farzipour S, Dehbanpour MR, Nosrati S. A review of effects of atorvastatin in cancer therapy. MEDICAL ONCOLOGY (NORTHWOOD, LONDON, ENGLAND) 2022; 40:27. [PMID: 36459301 DOI: 10.1007/s12032-022-01892-9] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/31/2022] [Accepted: 11/08/2022] [Indexed: 12/03/2022]
Abstract
Cancer is one of the most challenging diseases to manage. A sizeable number of researches are done each year to find better diagnostic and therapeutic strategies. At the present time, a package of chemotherapy, targeted therapy, radiotherapy, and immunotherapy is available to cope with cancer cells. Regarding chemo-radiation therapy, low effectiveness and normal tissue toxicity are like barriers against optimal response. To remedy the situation, some agents have been proposed as adjuvants to improve tumor responses. Statins, the known substances for reducing lipid, have shown a considerable capability for cancer treatment. Among them, atorvastatin as a reductase (HMG-CoA) inhibitor might affect proliferation, migration, and survival of cancer cells. Since finding an appropriate adjutant is of great importance, numerous studies have been conducted to precisely unveil antitumor effects of atorvastatin and its associated pathways. In this review, we aim to comprehensively review the most highlighted studies which focus on the use of atorvastatin in cancer therapy.
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Affiliation(s)
- Zahra Shaghaghi
- Cancer Research Center, Hamadan University of Medical Sciences, Hamadan, Iran.,Cardiovascular Research Center, Hamadan University of Medical Sciences, Hamadan, Iran
| | - Maryam Alvandi
- Cardiovascular Research Center, Hamadan University of Medical Sciences, Hamadan, Iran. .,Department of Nuclear Medicine and Molecular Imaging, School of Medicine, Hamadan University of Medical Sciences, Hamadan, Iran.
| | - Soghra Farzipour
- Department of Cardiology, Cardiovascular Diseases Research Center, School of Medicine, Heshmat Hospital, Guilan University of Medical Sciences, Rasht, Iran.,Department of Pharmaceutical Biotechnology, School of Pharmacy, Guilan University of Medical Sciences, Rasht, Iran
| | - Mohammad Reza Dehbanpour
- Department of Radiology, School of Paramedicine, Hamadan University of Medical Sciences, Hamadan, Iran
| | - Sahar Nosrati
- Institute of Nuclear Chemistry and Technology, Dorodna 16 Str, 03-195, Warsaw, Poland
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Interaction of human phospholipid scramblase 1 with cholesterol via CRAC motif is essential for functional regulation and subcellular localization. Int J Biol Macromol 2022; 209:850-857. [PMID: 35439477 DOI: 10.1016/j.ijbiomac.2022.04.087] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/27/2021] [Revised: 04/06/2022] [Accepted: 04/11/2022] [Indexed: 11/21/2022]
Abstract
Human phospholipid scramblase 1 (hPLSCR1) possesses a putative cholesterol binding CRAC (cholesterol interaction/recognition amino acid consensus) motif at the C-terminal. The CRAC motif of hPLSCR1 interacts with cholesterol with an energy of interaction -64.39 KJ mol-1. Since palmitoylated hPLSCR1 localizes to the cholesterol-rich lipid rafts, the interaction between hPLSCR1 and raft cholesterol is highly likely. The present study investigated the hPLSCR1-cholesterol interaction in plasma membrane via putative CRAC motif. hPLSCR1 remains at cholesterol-rich lipid rafts as long as they interact. This interaction is inhibited by mutations in the CRAC motif or cholesterol depletion. Thus, CRAC mutants I300D hPLSCR1 and ΔCRAC hPLSCR1 diffused to the cytoplasm and nucleus. Cholesterol depletion by methyl-β-cyclodextrin (MβCD) dose-dependently reduced cell viability in A549 cells. However, cholesterol depletion released 1.74 ± 0.12 times Ca2+ to the cytosol in A549 cells. Similarly, cholesterol depletion increased intracellular Ca2+ release by 1.81 ± 0.13 and 4.11 ± 0.19 times in RAJI cells expressing hPLSCR1 and ΔCRAC hPLSCR1, respectively. Moreover, the expression of hPLSCR1 and ΔCRAC hPLSCR1 increased apoptosis in RAJI cells by 21 ± 1.5% and 53.50 ± 4.40%, respectively. It was further increased to 43 ± 2.5% and 71.4 ± 1.4% upon cholesterol depletion. The current work links hPLSCR1 expression with cholesterol depletion, intracellular Ca2+ release, and induction of apoptosis.
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The mevalonate pathway in breast cancer biology. Cancer Lett 2022; 542:215761. [DOI: 10.1016/j.canlet.2022.215761] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2022] [Revised: 05/25/2022] [Accepted: 05/26/2022] [Indexed: 02/07/2023]
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Sim Y, Lim C, Phyu N, Tan KTB, Chew LST, Wong CY, Madhukumar P, Yong WS, Lim SZ, Hamzah JLB, Tan SY, Chay WY, Wong FY, Tan PH, Tan VKM. The Impact of Statin Use and Breast Cancer Recurrence - A Retrospective Study in Singapore. Front Oncol 2022; 12:835320. [PMID: 35433431 PMCID: PMC9008885 DOI: 10.3389/fonc.2022.835320] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2021] [Accepted: 03/07/2022] [Indexed: 11/13/2022] Open
Abstract
Introduction Statins, HMG-CoA reductase inhibitors, are commonly used cholesterol-lowering medications which are also increasingly recognized to have anti-cancer properties for various cancers, including breast cancer. Most clinical evidence supports a protective effect of statin on reducing breast cancer recurrence, particularly in hormone-receptor positive breast cancers.This study seeks to study the impact of statin use on breast cancer recurrence in an Asian population. Methods This is a retrospective study of patients diagnosed with breast cancer at the National Cancer Centre and Singapore General Hospital from 2005-2015. Statin use was defined as use after surgery. Associations between statin use, breast cancer recurrence and overall survival were estimated using Cox proportional hazards regression with adjustment for age, TNM stage, grade, ER/HER2 status, and co-morbidities. Associations between statin-use and disease-specific survival were estimated using competing risks regression. Results A total of 7858 females with breast cancer were studied, 1353(17.2%) were statin users, 6505(82.8%) were non-statin users, with a median follow-up of 8.67 years. Distribution of cancer stage, histology, molecular subtypes and grades were similar in both groups. Estrogen receptor(ER) positive (HR 0.57,95%CI 0.43-0.76,p<0.001) and HER2 negative (HR 0.74,95%CI 0.57-0.96,p=0.026) invasive cancers had a lower risk of recurrence in statin users. Statin users trended towards a long term recurrence-risk reduction (all subtypes,HR 0.48,p=0.002; ER-, HR 0.34,p=0.036; HER2+,HR 0.10,p=0.002). The risk-reduction benefit is not appreciated in statin users with DCIS, possibly due to small recurrence event numbers. Disease-specific survival benefit was seen in statin users with ER+ cancers (adjusted SHR 0.71,95%CI 0.53-0.96,p=0.027), especially ER+ invasive cancers (adjusted SHR 0.72, 95%CI 0.53-0.97,p=0.028), but with no statistically significant benefit in overall survival for statin users (all subtypes). Conclusion This is the first known retrospective study on the effect of statin use and breast cancer recurrence in an Asian population. Similar to previous international studies, statin use is associated with a risk reduction in breast cancer recurrence. This is especially beneficial in patients who have ER+ and HER2- invasive breast cancer. Statin use is also associated with a reduced risk of breast cancer recurrence in all subtypes of breast cancer in the long term (>6 years post diagnosis).
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Affiliation(s)
- Yirong Sim
- Department of Breast Surgery, Division of Surgery and Surgical Oncology, National Cancer Centre Singapore, Singapore, Singapore.,Department of Breast Surgery, Singapore General Hospital, Singapore, Singapore.,SingHealth Duke-National University of Singapore (NUS) Breast Centre, Singapore, Singapore
| | - Cindy Lim
- Clinical Trials and Epidemiological Sciences (CTE), National Cancer Centre Singapore, Singapore, Singapore
| | - Nitar Phyu
- Department of Cancer Informatics, National Cancer Centre Singapore, Singapore, Singapore
| | - Kiat Tee Benita Tan
- Department of Breast Surgery, Division of Surgery and Surgical Oncology, National Cancer Centre Singapore, Singapore, Singapore.,Department of Breast Surgery, Singapore General Hospital, Singapore, Singapore.,SingHealth Duke-National University of Singapore (NUS) Breast Centre, Singapore, Singapore.,Department of General Surgery, Sengkang General Hospital, Singapore, Singapore
| | - Lita Sui Tjien Chew
- Department of Pharmacy, National Cancer Center Singapore, Singapore, Singapore
| | - Chow Yin Wong
- Department of Breast Surgery, Singapore General Hospital, Singapore, Singapore.,SingHealth Duke-National University of Singapore (NUS) Breast Centre, Singapore, Singapore
| | - Preetha Madhukumar
- Department of Breast Surgery, Division of Surgery and Surgical Oncology, National Cancer Centre Singapore, Singapore, Singapore.,Department of Breast Surgery, Singapore General Hospital, Singapore, Singapore.,SingHealth Duke-National University of Singapore (NUS) Breast Centre, Singapore, Singapore
| | - Wei Sean Yong
- Department of Breast Surgery, Division of Surgery and Surgical Oncology, National Cancer Centre Singapore, Singapore, Singapore.,Department of Breast Surgery, Singapore General Hospital, Singapore, Singapore.,SingHealth Duke-National University of Singapore (NUS) Breast Centre, Singapore, Singapore
| | - Sue Zann Lim
- Department of Breast Surgery, Division of Surgery and Surgical Oncology, National Cancer Centre Singapore, Singapore, Singapore.,Department of Breast Surgery, Singapore General Hospital, Singapore, Singapore.,SingHealth Duke-National University of Singapore (NUS) Breast Centre, Singapore, Singapore
| | - Julie Liana Bte Hamzah
- Department of Breast Surgery, Division of Surgery and Surgical Oncology, National Cancer Centre Singapore, Singapore, Singapore.,Department of Breast Surgery, Singapore General Hospital, Singapore, Singapore.,SingHealth Duke-National University of Singapore (NUS) Breast Centre, Singapore, Singapore
| | - Si Ying Tan
- Department of Breast Surgery, Division of Surgery and Surgical Oncology, National Cancer Centre Singapore, Singapore, Singapore.,Department of Breast Surgery, Singapore General Hospital, Singapore, Singapore.,SingHealth Duke-National University of Singapore (NUS) Breast Centre, Singapore, Singapore
| | - Wen Yee Chay
- Division of Medical Oncology, National Cancer Centre Singapore, Singapore, Singapore
| | - Fuh Yong Wong
- Division of Radiation Oncology, National Cancer Centre Singapore, Singapore, Singapore
| | - Puay Hoon Tan
- Division of Pathology, Singapore General Hospital, Singapore, Singapore
| | - Veronique Kiak-Mien Tan
- Department of Breast Surgery, Division of Surgery and Surgical Oncology, National Cancer Centre Singapore, Singapore, Singapore.,Department of Breast Surgery, Singapore General Hospital, Singapore, Singapore.,SingHealth Duke-National University of Singapore (NUS) Breast Centre, Singapore, Singapore
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Use of Hypolipidemic Drugs and the Risk of Second Primary Malignancy in Colorectal Cancer Patients. Cancers (Basel) 2022; 14:cancers14071699. [PMID: 35406471 PMCID: PMC8997159 DOI: 10.3390/cancers14071699] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2022] [Revised: 03/17/2022] [Accepted: 03/24/2022] [Indexed: 11/25/2022] Open
Abstract
Simple Summary Hypolipidemic drugs are among the most frequently prescribed medications in the Western world. Since many studies have indicated their role in carcinogenesis, this work aimed to investigate their association with the occurrence of a second primary malignancy in colorectal cancer survivors. The overall incidence of a second neoplasm was not linked to hypolipidemic medication; however, a subgroup analysis revealed a lower incidence of secondary neoplasia in statin users. When stratified by cancer types, a significant increase in gastric and bladder cancer was detected among colorectal cancer patients using hypolipidemic drugs. Survival outcomes in patients with early-stage colorectal carcinoma who suffered second cancer were significantly worse if treated with hypolipidemic drugs. Although our results do not provide evidence for a causative relationship between hypolipidemic medication and carcinogenesis, these correlations might steer the direction of tertiary prevention care towards specific risk factors shared between cardiovascular diseases and cancer. Abstract An increasing number of studies has brought evidence of the protective role of statin use against different types of cancer. However, data on their association with second primary malignancies (SPMs) are lacking. The purpose of this study was to determine the role of hypolipidemic treatment in the prevention of second primary cancer in colorectal cancer (CRC) survivors. We conducted a retrospective single-institution study of 1401 patients with newly diagnosed colorectal cancer from January 2003 to December 2016, with follow-up until December 2020. An SPM was detected in 301 patients (21%), and the incidence was significantly lower in patients with statin medication. However, stratification by cancer types revealed an increased incidence of bladder and gastric cancer in hypolipidemic users. A Kaplan−Meier analysis of early-stage CRC survivors with an SPM showed a significant survival benefit in patients without a history of hypolipidemic treatment. Despite the protective role of statins on overall second cancer incidence, these data indicate that CRC survivors treated with hypolipidemic drugs should be screened more cautiously for SPMs, especially for gastric and bladder cancer.
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Relationship between serum lipid levels and the immune microenvironment in breast cancer patients: a retrospective study. BMC Cancer 2022; 22:167. [PMID: 35164691 PMCID: PMC8842971 DOI: 10.1186/s12885-022-09234-8] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2021] [Accepted: 01/19/2022] [Indexed: 12/17/2022] Open
Abstract
BACKGROUND Therapeutic agents for dyslipidaemia, in particular statins, have been recently reported to suppress growth and metastasis of breast cancer. However, the predictive value of lipid control in breast cancer patients has not been discussed sufficiently. In addition, though immunometabolism is a relatively novel approach for tumour immunotherapy, the relationship between lipid metabolism and immune status has not been well documented. We therefore investigated the effects of lipid metabolism on antitumour immune response and cancer prognosis. METHODS Except for patients with ductal carcinoma in situ, 938 patients treated with curative surgery were examined. The correlation between treatment for dyslipidaemia or serum lipid levels and clinicopathological features, including the prognosis, was evaluated retrospectively. Also, we stratified these results by intrinsic subtype of breast cancer, menopause, and type of therapeutic agents for dyslipidaemia. Moreover, neutrophil- to-lymphocyte ratio (NLR) and tumour-infiltrating lymphocytes (TILs) were used as indicators of systemic and local immune status, respectively. RESULTS Of 194 patients treated for dyslipidaemia, recurrence-free survival (RFS) and overall survival (OS) did not differ significantly between users of drugs for dyslipidaemia and non-users (p = 0.775 and p = 0.304, log-rank, respectively). Among postmenopausal, hormone receptor (HR)-positive/human epidermal growth factor receptor 2 (HER2)-negative breast cancer patients treated for dyslipidaemia, the good serum lipid control group had significantly better RFS (p = 0.014, log-rank), lower postoperative NLR (p = 0.012), and higher TILs in resected tissues (p = 0.024) than the poor control group. Multivariate analysis showed that postoperative serum lipid levels were a risk factor for recurrence (hazard ratio = 4.722, 95% confidence interval 1.006-22.161, p = 0.049). CONCLUSIONS Good control of serum lipid metabolism may improve the tumour immune microenvironment and prognosis in postmenopausal HR-positive/HER2-negative breast cancer patients.
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A chemokine regulatory loop induces cholesterol synthesis in lung-colonizing triple-negative breast cancer cells to fuel metastatic growth. Mol Ther 2022; 30:672-687. [PMID: 34274535 PMCID: PMC8821896 DOI: 10.1016/j.ymthe.2021.07.003] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2021] [Revised: 05/19/2021] [Accepted: 06/22/2021] [Indexed: 02/04/2023] Open
Abstract
Triple-negative breast cancer (TNBC) has a high propensity for organ-specific metastasis. However, the underlying mechanisms are not well understood. Here we show that the primary TNBC tumor-derived C-X-C motif chemokines 1/2/8 (CXCL1/2/8) stimulate lung-resident fibroblasts to produce the C-C motif chemokines 2/7 (CCL2/7), which, in turn, activate cholesterol synthesis in lung-colonizing TNBC cells and induce angiogenesis at lung metastatic sites. Inhibiting cholesterol synthesis in lung-colonizing breast tumor cells by pulmonary administration of simvastatin-carrying HER3-targeting nanoparticles reduces angiogenesis and growth of lung metastases in a syngeneic TNBC mouse model. Our findings reveal a novel, chemokine-regulated mechanism for the cholesterol synthesis pathway and a critical role of metastatic site-specific cholesterol synthesis in the pulmonary tropism of TNBC metastasis. The study has implications for the unresolved epidemiological observation that use of cholesterol-lowering drugs has no effect on breast cancer incidence but can unexpectedly reduce breast cancer mortality, suggesting interventions of cholesterol synthesis in lung metastases as an effective treatment to improve survival in individuals with TNBC.
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Inasu M, Feldt M, Jernström H, Borgquist S, Harborg S. Statin use and patterns of breast cancer recurrence in the Malmö Diet and Cancer Study. Breast 2022; 61:123-128. [PMID: 34995921 PMCID: PMC8741597 DOI: 10.1016/j.breast.2022.01.003] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2021] [Revised: 12/28/2021] [Accepted: 01/03/2022] [Indexed: 12/12/2022] Open
Abstract
BACKGROUND Accumulating evidence suggests that statins have a beneficial effect on breast cancer prognosis. Previous studies have reported a positive association between statin use and breast cancer survival; however, the relationship between statin use and patterns of breast cancer recurrence remains unclear. PATIENTS AND METHODS We identified all Malmö Diet and Cancer Study (MDCS) participants diagnosed with incident invasive breast cancer between 2005 and 2014. The follow-up period began at breast cancer diagnosis and continued until the first invasive breast cancer recurrence event, death, emigration or the end of the follow-up (June 8, 2020). We estimated incidence rates (IRs) of recurrence and fit Cox regression models to compute crude and adjusted hazard ratios (HRs) with 95% confidence intervals (95% CIs) for disease recurrence to compare post-diagnosis statin users with non-users. RESULTS The final study cohort consisted of 360 eligible patients with a median follow-up of 8.6 years. Overall, there were 71 recurrences in 2932 total person-years. According to statin use, there were 14 recurrences in 595 person-years among statin users, and 57 recurrences in 2337 person-years in non-users. Statin use was associated with a reduced risk of breast cancer recurrence (HRadj = 0.88 [95% CI: 0.82-0.96]). Regarding the pattern of recurrence, statin use was associated with a reduced risk of distant recurrence (HRadj = 0.86 [95% CI: 0.80-0.94]) but not loco-regional recurrence (HRadj = 0.97 [95% CI: 0.87-1.08]). CONCLUSION In the MDCS, statin use was associated with a reduced risk of distant breast cancer recurrence, whereas no association between statin use and loco-regional breast cancer recurrence was found. This site-based difference in disease recurrence may be explained by statin's inhibition of epithelial-mesenchymal transition.
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Affiliation(s)
- Maria Inasu
- Division of Oncology, Department of Clinical Sciences Lund, Lund University, Lund, Sweden.
| | - Maria Feldt
- Division of Oncology, Department of Clinical Sciences Lund, Lund University, Lund, Sweden
| | - Helena Jernström
- Division of Oncology, Department of Clinical Sciences Lund, Lund University, Lund, Sweden
| | - Signe Borgquist
- Division of Oncology, Department of Clinical Sciences Lund, Lund University, Lund, Sweden; Department of Oncology, Aarhus University/Aarhus University Hospital, Denmark
| | - Sixten Harborg
- Department of Oncology, Aarhus University/Aarhus University Hospital, Denmark.
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Zhao G, Ji Y, Ye Q, Ye X, Wo G, Chen X, Shao X, Tang J. Effect of statins use on risk and prognosis of breast cancer: a meta-analysis. Anticancer Drugs 2022; 33:e507-e518. [PMID: 34407042 DOI: 10.1097/cad.0000000000001151] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/27/2022]
Abstract
The findings regarding the association between statins use and breast cancer are inconsistent. Given the widely and long-term use of statins as first choice drug for dyslipidemia, we conducted this meta-analysis for better understanding the associations between statins use and the risk and prognosis of breast cancer. Articles regarding effect of statins use on risk, prognosis of breast cancer and published before January 2021 were searched in the following databases: Web of Science, PubMed, EMBASE, Medline and Google Scholar. Odds ratios (ORs)/relative risks (RRs) or hazard ratios (HRs) and their 95% confidence intervals (CIs) were computed to generate a pooled effect size and 95% CI. The meta-analysis showed no significant association between statins use and risk of breast cancer (OR/RR = 1.02; 95% CI, 0.97-1.08; I2 = 76.1%; P < 0.001). The meta-analysis showed that statins use was associated with lower breast cancer recurrence, all-cause mortality and disease-specific mortality (breast cancer recurrence: HR = 0.75; 95% CI, 0.67-0.84; I2 = 31.7%; P = 0.154; all-cause mortality: HR = 0.82; 95% CI, 0.77-0.89; I2 = 67.5%; P < 0.001; and disease-specific mortality: HR = 0.82; 95% CI, 0.72-0.93; I2 = 83.6%; P < 0.001). Overall, in this report we demonstrated that the use of statins can improve the prognosis of breast cancer patients including lower risks of breast cancer recurrence, all-cause and cancer-specific mortality, though statins therapy may not have an impact on reducing the risk of breast cancer.
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Affiliation(s)
- Guodong Zhao
- Nanjing University of Chinese Medicine, Nanjing
- Department of General Surgery and Department of Oncology, Lianshui County People's Hospital, Huaian, Jiangsu, China
| | - Yanjun Ji
- Department of General Surgery and Department of Oncology, Lianshui County People's Hospital, Huaian, Jiangsu, China
| | - Qing Ye
- Department of General Surgery and Department of Oncology, Lianshui County People's Hospital, Huaian, Jiangsu, China
| | - Xin Ye
- Department of General Surgery and Department of Oncology, Lianshui County People's Hospital, Huaian, Jiangsu, China
| | - Guanqun Wo
- Nanjing University of Chinese Medicine, Nanjing
| | - Xi Chen
- Nanjing University of Chinese Medicine, Nanjing
| | - Xinyi Shao
- Nanjing University of Chinese Medicine, Nanjing
| | - Jinhai Tang
- Nanjing University of Chinese Medicine, Nanjing
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Nowakowska MK, Lei X, Thompson MT, Shaitelman SF, Wehner MR, Woodward WA, Giordano SH, Nead KT. Association of statin use with clinical outcomes in patients with triple-negative breast cancer. Cancer 2021; 127:4142-4150. [PMID: 34342892 PMCID: PMC11912801 DOI: 10.1002/cncr.33797] [Citation(s) in RCA: 37] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2021] [Revised: 06/20/2021] [Accepted: 06/24/2021] [Indexed: 01/06/2023]
Abstract
BACKGROUND Previous studies have examined the association of statin therapy and breast cancer outcomes with mixed results. The objective of this study was to investigate the clinical effects of incident statin use among individuals with triple-negative breast cancer (TNBC). METHODS Data from the Surveillance, Epidemiology, and End Results-Medicare and Texas Cancer Registry-Medicare databases were used, and women aged ≥66 years who had stage I, II, and III breast cancer were identified. Multivariable Cox proportional hazards regression models were used to examine the association of new statin use in the 12 months after a breast cancer diagnosis with overall survival (OS) and breast cancer-specific survival (BCSS). RESULTS When examining incident statin use, defined as the initiation of statin therapy in the 12 months after breast cancer diagnosis, a significant association was observed between statin use and improved BCSS (standardized hazard ratio, 0.42; 95% confidence interval [CI], 0.20-0.88; P = .022) and OS (hazard ratio, 0.70; 95% CI, 0.50-0.99; P = .046) among patients with TNBC (n = 1534). No association was observed with BCSS (standardized hazard ratio, 0.99; 95% CI, 0.71-1.39; P = .97) or OS (hazard ratio, 1.04; 95% CI, 0.92-1.17; P = .55) among those without TNBC (n = 15,979). The results were consistent when examining statin exposure as a time-varying variable. CONCLUSIONS Among women with I, II, and III TNBC, initiation of statin therapy in the 12 months after breast cancer diagnosis was associated with an OS and BCSS benefit. Statins may have a role in select patients with breast cancer, and further investigation is warranted.
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Affiliation(s)
| | - Xiudong Lei
- Department of Health Services Research, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Mikayla T Thompson
- School of Public Health and Health Professions, University at Buffalo, Buffalo, New York
| | - Simona F Shaitelman
- Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Mackenzie R Wehner
- Department of Health Services Research, The University of Texas MD Anderson Cancer Center, Houston, Texas
- Department of Dermatology, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Wendy A Woodward
- Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Sharon H Giordano
- Department of Health Services Research, The University of Texas MD Anderson Cancer Center, Houston, Texas
- Department of Breast Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Kevin T Nead
- Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas
- Department of Epidemiology, The University of Texas MD Anderson Cancer Center, Houston, Texas
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Moksud N, Loo LWM, Yang J, Huang CY, Haiman CA, Le Marchand L, Wilkens LR, Cheng I. Cholesterol lowering drug use and breast cancer survival: the Multiethnic Cohort Study. Breast Cancer Res Treat 2021; 190:165-173. [PMID: 34460030 PMCID: PMC8557195 DOI: 10.1007/s10549-021-06360-y] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2021] [Accepted: 08/08/2021] [Indexed: 12/17/2022]
Abstract
PURPOSE Prior studies conducted primarily in white populations have suggested that pre-diagnostic cholesterol lowering drugs (CLDs) improved survival among women with breast cancer (BC). However, this association had not been well characterized in diverse racial/ethnic populations. We investigated whether pre-diagnostic CLD use is associated with all-cause and BC-specific mortality among female BC cases of the Multiethnic Cohort (MEC). METHODS CLD use was ascertained through questionnaires administered in 2003-2008. A total of 1448 incident BC cases were identified by linkage to SEER cancer registries in Hawaii and California from 2003 to 2014. Multivariable Cox regression was conducted to estimate hazard ratios (HR) and 95% confidence intervals (CI) of the associations of pre-diagnostic CLD use with all-cause and BC-specific mortality, adjusting for tumor characteristics, first course of treatment, health behaviors, co-morbidities, and demographics. Subgroup analyses by stage and hormone receptor status were conducted for all-cause mortality. RESULTS There were 224 all-cause and 87 BC-specific deaths among the 1448 BC cases during a median follow-up of 4.5 years after diagnosis. Women with BC who ever used CLDs had a 27% lower hazard of all-cause mortality (HR 0.73, 95% CI 0.54-0.98) and 17% lower hazard of BC-specific mortality (HR 0.83, 95% CI 0.49-1.39) compared to never users. CLD use reduced mortality among women with advanced-stage tumors and hormone receptor-positive breast tumors (HR 0.54 95% CI 0.33-0.90; HR 0.69, 95% CI 0.48-0.99, respectively). CONCLUSION These findings demonstrate an improved survival associated with CLD use prior to diagnosis in a multiethnic population of women with BC.
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Affiliation(s)
- Nafeesa Moksud
- Department of Epidemiology and Biostatistics, University of California, San Francisco, 550 16th Street, San Francisco, CA, 94158, USA
| | - Lenora W M Loo
- Cancer Biology Program, University of Hawaii Cancer Center, Honolulu, HI, USA
| | - Juan Yang
- Department of Epidemiology and Biostatistics, University of California, San Francisco, 550 16th Street, San Francisco, CA, 94158, USA
| | - Chiung-Yu Huang
- Department of Epidemiology and Biostatistics, University of California, San Francisco, 550 16th Street, San Francisco, CA, 94158, USA
| | - Christopher A Haiman
- Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA
| | - Loïc Le Marchand
- Population Sciences in the Pacific Program, University of Hawaii Cancer Center, Honolulu, HI, USA
| | - Lynne R Wilkens
- Population Sciences in the Pacific Program, University of Hawaii Cancer Center, Honolulu, HI, USA
| | - Iona Cheng
- Department of Epidemiology and Biostatistics, University of California, San Francisco, 550 16th Street, San Francisco, CA, 94158, USA.
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Inasu M, Bendahl PO, Fernö M, Malmström P, Borgquist S, Kimbung S. High CYP27A1 expression is a biomarker of favorable prognosis in premenopausal patients with estrogen receptor positive primary breast cancer. NPJ Breast Cancer 2021; 7:127. [PMID: 34556659 PMCID: PMC8460751 DOI: 10.1038/s41523-021-00333-6] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2021] [Accepted: 08/20/2021] [Indexed: 01/03/2023] Open
Abstract
27-hydroxycholesterol (27HC), synthesized from cholesterol by the enzyme CYP27A1, differentially impacts estrogen receptor positive (ER+) breast cancer (BC) cell growth depending on estrogen levels. This study examined the association between CYP27A1 expression and prognosis in a cohort of 193 premenopausal patients with lymph node-negative primary BC with limited exposure to adjuvant systemic cancer treatments. In multivariable analyses among patients with ER+ tumors, high CYP27A1 protein and mRNA expressions were associated with four- and eight-fold reductions in the incidence of distant recurrence-free survival events: HRadj = 0.26, 95% CI = 0.07-0.93 and HRadj = 0.13, 95% CI = 0.03-0.60, respectively. In vitro studies revealed that 27HC treatment potently inhibited ER+ BC cell proliferation under lipid-depleted conditions regardless of estradiol levels, transcriptionally mediated through the downregulation of ER signaling with a concomitant upregulation of cholesterol export. Importantly, if validated, these results may have implications for adjuvant treatment decisions in premenopausal patients, especially when de-escalation of therapy is being considered.
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Affiliation(s)
- Maria Inasu
- Division of Oncology, Department of Clinical Sciences Lund, Lund University, Lund, Sweden
| | - Pär-Ola Bendahl
- Division of Oncology, Department of Clinical Sciences Lund, Lund University, Lund, Sweden
| | - Mårten Fernö
- Division of Oncology, Department of Clinical Sciences Lund, Lund University, Lund, Sweden
| | - Per Malmström
- Division of Oncology, Department of Clinical Sciences Lund, Lund University, Lund, Sweden.,Department of Hematology, Oncology and Radiation Physics, Skåne University Hospital, Lund, Sweden
| | - Signe Borgquist
- Division of Oncology, Department of Clinical Sciences Lund, Lund University, Lund, Sweden.,Department of Oncology, Aarhus University and Aarhus University Hospital, Aarhus, Denmark
| | - Siker Kimbung
- Division of Oncology, Department of Clinical Sciences Lund, Lund University, Lund, Sweden.
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Barbălată CI, Porfire AS, Sesarman A, Rauca VF, Banciu M, Muntean D, Știufiuc R, Moldovan A, Moldovan C, Tomuță I. A Screening Study for the Development of Simvastatin-Doxorubicin Liposomes, a Co-Formulation with Future Perspectives in Colon Cancer Therapy. Pharmaceutics 2021; 13:pharmaceutics13101526. [PMID: 34683821 PMCID: PMC8537800 DOI: 10.3390/pharmaceutics13101526] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2021] [Revised: 09/08/2021] [Accepted: 09/15/2021] [Indexed: 01/25/2023] Open
Abstract
An increasing number of studies published so far have evidenced the benefits of Simvastatin (SIM) and Doxorubicin (DOX) co-treatment in colorectal cancer. In view of this, the current study aimed to investigate the pharmaceutical development of liposomes co-encapsulating SIM and DOX, by implementing the Quality by Design (QbD) concept, as a means to enhance the antiproliferative effect of the co-formulation on C26 murine colon cancer cells co-cultured with macrophages. It is known that the quality profile of liposomes is dependent on the critical quality attributes (CQAs) of liposomes (drug entrapped concentration, encapsulation efficiency, size, zeta potential, and drug release profile), which are, in turn, directly influenced by various formulation factors and processing parameters. By using the design of experiments, it was possible to outline the increased variability of CQAs in relation to formulation factors and identify by means of statistical analysis the material attributes that are critical (phospholipids, DOX and SIM concentration) for the quality of the co-formulation. The in vitro studies performed on a murine colon cancer cell line highlighted the importance of delivering the optimal drug ratio at the target site, since the balance antiproliferative vs. pro-proliferative effects can easily be shifted when the molar ratio between DOX and SIM changes.
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Affiliation(s)
- Cristina Ioana Barbălată
- Pharmaceutical Technology and Biopharmaceutics, Faculty of Pharmacy, Iuliu Hațieganu University of Medicine and Pharmacy, 41 Victor Babes Street, 400012 Cluj-Napoca, Romania; (C.I.B.); (D.M.); (I.T.)
| | - Alina Silvia Porfire
- Pharmaceutical Technology and Biopharmaceutics, Faculty of Pharmacy, Iuliu Hațieganu University of Medicine and Pharmacy, 41 Victor Babes Street, 400012 Cluj-Napoca, Romania; (C.I.B.); (D.M.); (I.T.)
- Correspondence:
| | - Alina Sesarman
- Department of Molecular Biology and Biotechnology, Centre for Systems Biology, Biodiversity and Bioresources (3B), Faculty of Biology and Geology, Babes-Bolyai University, 5-7 Clinicilor Street, 400006 Cluj-Napoca, Romania; (A.S.); (V.-F.R.); (M.B.)
- Molecular Biology Center, Institute for Interdisciplinary Research in Bio-Nano-Sciences of Babes-Bolyai University, 42 Treboniu Laurian Street, 400271 Cluj-Napoca, Romania
| | - Valentin-Florian Rauca
- Department of Molecular Biology and Biotechnology, Centre for Systems Biology, Biodiversity and Bioresources (3B), Faculty of Biology and Geology, Babes-Bolyai University, 5-7 Clinicilor Street, 400006 Cluj-Napoca, Romania; (A.S.); (V.-F.R.); (M.B.)
- Molecular Biology Center, Institute for Interdisciplinary Research in Bio-Nano-Sciences of Babes-Bolyai University, 42 Treboniu Laurian Street, 400271 Cluj-Napoca, Romania
| | - Manuela Banciu
- Department of Molecular Biology and Biotechnology, Centre for Systems Biology, Biodiversity and Bioresources (3B), Faculty of Biology and Geology, Babes-Bolyai University, 5-7 Clinicilor Street, 400006 Cluj-Napoca, Romania; (A.S.); (V.-F.R.); (M.B.)
- Molecular Biology Center, Institute for Interdisciplinary Research in Bio-Nano-Sciences of Babes-Bolyai University, 42 Treboniu Laurian Street, 400271 Cluj-Napoca, Romania
| | - Dana Muntean
- Pharmaceutical Technology and Biopharmaceutics, Faculty of Pharmacy, Iuliu Hațieganu University of Medicine and Pharmacy, 41 Victor Babes Street, 400012 Cluj-Napoca, Romania; (C.I.B.); (D.M.); (I.T.)
| | - Rareș Știufiuc
- MedFuture Research Center for Advanced Medicine, Iuliu Hatieganu University of Medicine and Pharmacy, 4-6 Louis Pasteur Street, 400337 Cluj-Napoca, Romania; (R.Ș.); (A.M.); (C.M.)
| | - Alin Moldovan
- MedFuture Research Center for Advanced Medicine, Iuliu Hatieganu University of Medicine and Pharmacy, 4-6 Louis Pasteur Street, 400337 Cluj-Napoca, Romania; (R.Ș.); (A.M.); (C.M.)
| | - Cristian Moldovan
- MedFuture Research Center for Advanced Medicine, Iuliu Hatieganu University of Medicine and Pharmacy, 4-6 Louis Pasteur Street, 400337 Cluj-Napoca, Romania; (R.Ș.); (A.M.); (C.M.)
| | - Ioan Tomuță
- Pharmaceutical Technology and Biopharmaceutics, Faculty of Pharmacy, Iuliu Hațieganu University of Medicine and Pharmacy, 41 Victor Babes Street, 400012 Cluj-Napoca, Romania; (C.I.B.); (D.M.); (I.T.)
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Asif K, Memeo L, Palazzolo S, Frión-Herrera Y, Parisi S, Caligiuri I, Canzonieri V, Granchi C, Tuccinardi T, Rizzolio F. STARD3: A Prospective Target for Cancer Therapy. Cancers (Basel) 2021; 13:4693. [PMID: 34572920 PMCID: PMC8472075 DOI: 10.3390/cancers13184693] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2021] [Accepted: 09/10/2021] [Indexed: 12/24/2022] Open
Abstract
Cancer is one of the major causes of death in developed countries and current therapies are based on surgery, chemotherapeutic agents, and radiation. To overcome side effects induced by chemo- and radiotherapy, in recent decades, targeted therapies have been proposed in second and even first lines. Targeted drugs act on the essential pathways involved in tumor induction, progression, and metastasis, basically all the hallmark of cancers. Among emerging pathways, the cholesterol metabolic pathway is a strong candidate for this purpose. Cancer cells have an accelerated metabolic rate and require a continuous supply of cholesterol for cell division and membrane renewal. Steroidogenic acute regulatory related lipid transfer (START) proteins are a family of proteins involved in the transfer of lipids and some of them are important in non-vesicular cholesterol transportation within the cell. The alteration of their expression levels is implicated in several diseases, including cancers. In this review, we report the latest discoveries on StAR-related lipid transfer protein domain 3 (STARD3), a member of the START family, which has a potential role in cancer, focusing on the structural and biochemical characteristics and mechanisms that regulate its activity. The role of the STARD3 protein as a molecular target for the development of cancer therapies is also discussed. As STARD3 is a key protein in the cholesterol movement in cancer cells, it is of interest to identify inhibitors able to block its activity.
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Affiliation(s)
- Kanwal Asif
- Department of Molecular Sciences and Nanosystems, PhD School in Science and Technology of Bio and Nanomaterials, Ca’ Foscari University of Venice, 30172 Venice, Italy;
- Pathology Unit, Centro di Riferimento Oncologico di Aviano (C.R.O.) IRCCS, 33081 Aviano, Italy; (S.P.); (S.P.); (V.C.)
| | - Lorenzo Memeo
- Department of Experimental Oncology, Mediterranean Institute of Oncology, 95029 Catania, Italy;
| | - Stefano Palazzolo
- Pathology Unit, Centro di Riferimento Oncologico di Aviano (C.R.O.) IRCCS, 33081 Aviano, Italy; (S.P.); (S.P.); (V.C.)
| | - Yahima Frión-Herrera
- Department of Molecular Sciences and Nanosystems, Ca’ Foscari University of Venice, 30172 Venice, Italy; or
| | - Salvatore Parisi
- Pathology Unit, Centro di Riferimento Oncologico di Aviano (C.R.O.) IRCCS, 33081 Aviano, Italy; (S.P.); (S.P.); (V.C.)
| | - Isabella Caligiuri
- Pathology Unit, Centro di Riferimento Oncologico di Aviano (C.R.O.) IRCCS, 33081 Aviano, Italy; (S.P.); (S.P.); (V.C.)
| | - Vincenzo Canzonieri
- Pathology Unit, Centro di Riferimento Oncologico di Aviano (C.R.O.) IRCCS, 33081 Aviano, Italy; (S.P.); (S.P.); (V.C.)
- Department of Medical, Surgical and Health Sciences, University of Trieste, 34149 Trieste, Italy
| | - Carlotta Granchi
- Department of Pharmacy, University of Pisa, 56126 Pisa, Italy; (C.G.); (T.T.)
| | - Tiziano Tuccinardi
- Department of Pharmacy, University of Pisa, 56126 Pisa, Italy; (C.G.); (T.T.)
| | - Flavio Rizzolio
- Pathology Unit, Centro di Riferimento Oncologico di Aviano (C.R.O.) IRCCS, 33081 Aviano, Italy; (S.P.); (S.P.); (V.C.)
- Department of Molecular Sciences and Nanosystems, Ca’ Foscari University of Venice, 30172 Venice, Italy; or
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Atorvastatin facilitates chemotherapy effects in metastatic triple-negative breast cancer. Br J Cancer 2021; 125:1285-1298. [PMID: 34462586 DOI: 10.1038/s41416-021-01529-0] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2021] [Revised: 07/12/2021] [Accepted: 08/12/2021] [Indexed: 12/12/2022] Open
Abstract
BACKGROUND Metastatic triple-negative breast cancer (mTNBC) is treated mainly with chemotherapy. However, resistance frequently occurs as tumours enter dormancy. Statins have been suggested as effective against cancer but as they prolong and promote dormancy, it is an open question of whether the concomitant use would interfere with chemotherapy in primary and mTNBC. We examined this question in animal models and clinical correlations. METHODS We used a xenograft model of spontaneous metastasis to the liver from an ectopic tumour employing a mTNBC cell line. Atorvastatin was provided to sensitise metastatic cells, followed by chemotherapy. The effects of statin usage on outcomes in women with metastatic breast cancer was assessed respectively by querying a database of those diagnosed from 1999 to 2019. RESULTS Atorvastatin had limited influence on tumour growth or chemotherapy effects in ectopic primary tumours. Interestingly, atorvastatin was additive with doxorubicin (but not paclitaxel) when targeting liver metastases. E-cadherin-expressing, dormant, breast cancer cells were resistant to the use of either statins or chemotherapy as compared to wild-type cells; however, the combination of both did lead to increased cell death. Although prospective randomised studies are needed for validation, our retrospective clinical analysis suggested that patients on statin treatment could experience prolonged dormancy and overall survival; still once the tumour recurred progression was not affected by statin use. CONCLUSION Atorvastatin could be used during adjuvant chemotherapy and also in conjunction with metastatic chemotherapy to reduce mTNBC cancer progression. These preclinical data establish a rationale for the development of randomised studies.
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Mahboobnia K, Pirro M, Marini E, Grignani F, Bezsonov EE, Jamialahmadi T, Sahebkar A. PCSK9 and cancer: Rethinking the link. Biomed Pharmacother 2021; 140:111758. [PMID: 34058443 DOI: 10.1016/j.biopha.2021.111758] [Citation(s) in RCA: 59] [Impact Index Per Article: 14.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2021] [Revised: 05/17/2021] [Accepted: 05/20/2021] [Indexed: 12/18/2022] Open
Abstract
BACKGROUND Cancer is emerging as a major problem globally, as it accounts for the second cause of death despite medical advances. According to epidemiological and basic studies, cholesterol is involved in cancer progression and there are abnormalities in cholesterol metabolism of cancer cells including prostate, breast, and colorectal carcinomas. However, the importance of cholesterol in carcinogenesis and thereby the role of cholesterol homeostasis as a therapeutic target is still a debated area in cancer therapy. Proprotein convertase subtilisin/kexin type-9 (PCSK9), a serine protease, modulates cholesterol metabolism by attachment to the LDL receptor (LDLR) and reducing its recycling by targeting the receptor for lysosomal destruction. Published research has shown that PCSK9 is also involved in degradation of other LDLR family members namely very-low-density-lipoprotein receptor (VLDLR), lipoprotein receptor-related protein 1 (LRP-1), and apolipoprotein E receptor 2 (ApoER2). As a result, this protein represents an interesting therapeutic target for the treatment of hypercholesterolemia. Interestingly, clinical trials on PCSK9-specific monoclonal antibodies have reported promising results with high efficacy in lowering LDL-C and in turn reducing cardiovascular complications. It is important to note that PCSK9 mediates several other pathways apart from its role in lipid homeostasis, including antiviral activity, hepatic regeneration, neuronal apoptosis, and modulation of various signaling pathways. Furthermore, recent literature has illustrated that PCSK9 is closely associated with incidence and progression of several cancers. In a number of studies, PCSK9 siRNA was shown to effectively suppress the proliferation and invasion of the several studied tumor cells. Hence, a novel application of PCSK9 inhibitors/silencers in cancer/metastasis could be considered. However, due to poor data on effectiveness and safety of PCSK9 inhibitors in cancer, the impact of PCSK9 inhibition in these pathological conditions is still unknown. SEARCH METHODS A vast literature search was conducted to find intended studies from 1956 up to 2020, and inclusion criteria were original peer-reviewed publications. PURPOSE OF REVIEW To date, PCSK9 has been scantly investigated in cancer. The question that needs to be discussed is "How does PCSK9 act in cancer pathophysiology and what are the risks or benefits associated to its inhibition?". We reviewed the available publications highlighting the contribution of this proprotein convertase in pathways related to cancer, with focus on the potential implications of its long-term pharmacological inhibition in cancer therapy.
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Affiliation(s)
- Khadijeh Mahboobnia
- Department of Biochemistry, Faculty of Medicine, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
| | - Matteo Pirro
- Unit of Internal Medicine, Angiology and Arteriosclerosis Diseases, Department of Medicine, University of Perugia, Perugia, Italy
| | - Ettore Marini
- Unit of Internal Medicine, Angiology and Arteriosclerosis Diseases, Department of Medicine, University of Perugia, Perugia, Italy
| | - Francesco Grignani
- Unit of Internal Medicine, Angiology and Arteriosclerosis Diseases, Department of Medicine, University of Perugia, Perugia, Italy
| | - Evgeny E Bezsonov
- Laboratory of Cellular and Molecular Pathology of Cardiovascular System, Institute of Human Morphology, 3 Tsyurupa Street, Moscow 117418, Russia; Laboratory of Angiopathology, Institute of General Pathology and Pathophysiology, 8 Baltiiskaya Street, Moscow 125315, Russia
| | - Tannaz Jamialahmadi
- Department of Food Science and Technology, Quchan Branch, Islamic Azad University, Quchan, Iran; Department of Nutrition, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Amirhossein Sahebkar
- Applied Biomedical Research Center, Mashhad University of Medical Sciences, Mashhad, Iran; Biotechnology Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran; School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran.
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Hanley GE, Kaur P, Berchuck A, Chase A, Grout B, Deurloo CM, Pike M, Richardson J, Terry KL, Webb PM, Pearce CL. Cardiovascular medications and survival in people with ovarian cancer: A population-based cohort study from British Columbia, Canada. Gynecol Oncol 2021; 162:461-468. [PMID: 34090707 PMCID: PMC9398205 DOI: 10.1016/j.ygyno.2021.05.021] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2021] [Accepted: 05/20/2021] [Indexed: 11/23/2022]
Abstract
OBJECTIVES Research examining survival among people with ovarian cancer following use of statins or β-blockers has been conflicting. Many studies to date have suffered from immortal time bias and/or had limited power. To address these limitations, we used time-dependent analyses to study the association between statin or β-blocker use among all people diagnosed with an epithelial ovarian cancer in British Columbia, Canada between 1997 and 2015. METHODS Population-based administrative data were linked for 4207 people with ovarian cancer. Statin or β-blocker use was examined using time-dependent variables for any use, cumulative duration of use and by user-group according to whether use was initiated before or after their ovarian cancer diagnosis. Cox proportional hazards models were run to estimate the association between statin or β-blocker use and survival. RESULTS Any postdiagnosis use of statins was associated with better ovarian cancer survival in the full cohort (adjusted hazard ratio (aHR) = 0.76, 95% CI 0.64, 0.89) and among women with serous cancers (aHR = 0.80, 95%CI 0.67-0.96). This was primarily driven by new use post-diagnosis (aHR = 0.67, 95%CI, 0.51-0.89), but there was a trend towards better survival among those who continued use from before diagnosis (aHR 0.83, 95%CI, 0.68-1.00). There was no statistically significant association between β-blocker use and survival. CONCLUSION Postdiagnosis statin use was associated with improved survival among people with ovarian cancer. Given the consistency of this finding in the literature, we recommend a randomized clinical trial of statin use in people with ovarian cancer.
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Affiliation(s)
- Gillian E Hanley
- Department of Gynaecology and Obstetrics, Division of Gynaecologic Oncology, University of British Columbia, Vancouver, BC, Canada.
| | - Paramdeep Kaur
- Department of Gynaecology and Obstetrics, Division of Gynaecologic Oncology, University of British Columbia, Vancouver, BC, Canada
| | - Andrew Berchuck
- Department of Gynecologic Oncology, Duke University Medical Center, Durham, NC, United States
| | | | | | | | - Malcolm Pike
- Memorial Sloan Kettering, New York, NY, United States; Department of Preventive Medicine, University of Southern California, Los Angeles, CA, United States
| | - Jean Richardson
- Department of Preventive Medicine, University of Southern California, Los Angeles, CA, United States
| | - Kathryn L Terry
- Department of Epidemiology, Harvard TH Chan School of Public Health, Boston, MA, United States; Obstetrics and Gynecology Epidemiology Center, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, United States
| | - Penelope M Webb
- Population Health Department, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia
| | - C Leigh Pearce
- Department of Epidemiology, School of Public Health, University of Michigan, Ann Arbor, MI, United States
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Garcia-Ruiz C, Conde de la Rosa L, Ribas V, Fernandez-Checa JC. MITOCHONDRIAL CHOLESTEROL AND CANCER. Semin Cancer Biol 2021; 73:76-85. [PMID: 32805396 PMCID: PMC7882000 DOI: 10.1016/j.semcancer.2020.07.014] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2020] [Revised: 07/22/2020] [Accepted: 07/29/2020] [Indexed: 12/11/2022]
Abstract
Cholesterol is a crucial component of membrane bilayers that determines their physical and functional properties. Cells largely satisfy their need for cholesterol through the novo synthesis from acetyl-CoA and this demand is particularly critical for cancer cells to sustain dysregulated cell proliferation. However, the association between serum or tissue cholesterol levels and cancer development is not well established as epidemiologic data do not consistently support this link. While most preclinical studies focused on the role of total celular cholesterol, the specific contribution of the mitochondrial cholesterol pool to alterations in cancer cell biology has been less explored. Although low compared to other bilayers, the mitochondrial cholesterol content plays an important physiological function in the synthesis of steroid hormones in steroidogenic tissues or bile acids in the liver and controls mitochondrial function. In addition, mitochondrial cholesterol metabolism generates oxysterols, which in turn, regulate multiple pathways, including cholesterol and lipid metabolism as well as cell proliferation. In the present review, we summarize the regulation of mitochondrial cholesterol, including its role in mitochondrial routine performance, cell death and chemotherapy resistance, highlighting its potential contribution to cancer. Of particular relevance is hepatocellular carcinoma, whose incidence in Western countries had tripled in the past decades due to the obesity and type II diabetes epidemic. A better understanding of the role of mitochondrial cholesterol in cancer development may open up novel opportunities for cancer therapy.
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Affiliation(s)
- Carmen Garcia-Ruiz
- Department of Cell Death and Proliferation, Institute of Biomedical Research of Barcelona (IIBB), CSIC, Barcelona, Spain; Liver Unit, Hospital Clinic I Provincial de Barcelona, Instituto de Investigaciones Biomédicas August Pi i Sunyer (IDIBAPS), Barcelona, Spain; Center for the Study of Liver and Gastrointestinal Diseases (CIBERehd), Carlos III National Institute of Health, Madrid, Spain; Center for ALPD, Keck School of Medicine, University of Southern California, Los Angeles, CA, United States
| | - Laura Conde de la Rosa
- Department of Cell Death and Proliferation, Institute of Biomedical Research of Barcelona (IIBB), CSIC, Barcelona, Spain; Liver Unit, Hospital Clinic I Provincial de Barcelona, Instituto de Investigaciones Biomédicas August Pi i Sunyer (IDIBAPS), Barcelona, Spain; Center for the Study of Liver and Gastrointestinal Diseases (CIBERehd), Carlos III National Institute of Health, Madrid, Spain
| | - Vicent Ribas
- Department of Cell Death and Proliferation, Institute of Biomedical Research of Barcelona (IIBB), CSIC, Barcelona, Spain; Liver Unit, Hospital Clinic I Provincial de Barcelona, Instituto de Investigaciones Biomédicas August Pi i Sunyer (IDIBAPS), Barcelona, Spain; Center for the Study of Liver and Gastrointestinal Diseases (CIBERehd), Carlos III National Institute of Health, Madrid, Spain
| | - Jose C Fernandez-Checa
- Department of Cell Death and Proliferation, Institute of Biomedical Research of Barcelona (IIBB), CSIC, Barcelona, Spain; Liver Unit, Hospital Clinic I Provincial de Barcelona, Instituto de Investigaciones Biomédicas August Pi i Sunyer (IDIBAPS), Barcelona, Spain; Center for the Study of Liver and Gastrointestinal Diseases (CIBERehd), Carlos III National Institute of Health, Madrid, Spain; Center for ALPD, Keck School of Medicine, University of Southern California, Los Angeles, CA, United States
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Baek AE, Krawczynska N, Das Gupta A, Dvoretskiy SV, You S, Park J, Deng YH, Sorrells JE, Smith BP, Ma L, Nelson AT, McDowell HB, Sprenger A, Henn MA, Madak-Erdogan Z, Kong H, Boppart SA, Boppart MD, Nelson ER. The Cholesterol Metabolite 27HC Increases Secretion of Extracellular Vesicles Which Promote Breast Cancer Progression. Endocrinology 2021; 162:6271123. [PMID: 33959755 PMCID: PMC8197285 DOI: 10.1210/endocr/bqab095] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/02/2021] [Indexed: 12/19/2022]
Abstract
Cholesterol has been implicated in the clinical progression of breast cancer, a disease that continues to be the most commonly diagnosed cancer in women. Previous work has identified the cholesterol metabolite 27-hydroxycholesterol (27HC) as a major mediator of the effects of cholesterol on breast tumor growth and progression. 27HC can act as an estrogen receptor (ER) modulator to promote the growth of ERα+ tumors, and as a liver X receptor (LXR) ligand in myeloid immune cells to establish an immune-suppressive program. In fact, the metastatic properties of 27HC require the presence of myeloid cells with neutrophils (polymorphonuclear neutrophils; PMNs) being essential for the increase in lung metastasis in murine models. In an effort to further elucidate the mechanisms by which 27HC alters breast cancer progression, we made the striking finding that 27HC promoted the secretion of extracellular vesicles (EVs), a diverse assortment of membrane bound particles that includes exosomes. The resulting EVs had a size distribution that was skewed slightly larger than EVs generated by treating cells with vehicle. The increase in EV secretion and size was consistent across 3 different subtypes: primary murine PMNs, RAW264.7 monocytic cells, and 4T1 murine mammary cancer cells. Label-free analysis of 27HC-EVs indicated that they had a different metabolite composition to those from vehicle-treated cells. Importantly, 27HC-EVs from primary PMNs promoted tumor growth and metastasis in 2 different syngeneic models, demonstrating the potential role of 27HC-induced EVs in the progression of breast cancer. EVs from PMNs were taken up by cancer cells, macrophages, and PMNs, but not T cells. Since EVs did not alter proliferation of cancer cells, it is likely that their protumor effects are mediated through interactions with myeloid cells. Interestingly, RNA-seq analysis of tumors from 27HC-EV-treated mice do not display significantly altered transcriptomes, suggesting that the effects of 27HC-EVs occur early on in tumor establishment and growth. Future work will be required to elucidate the mechanisms by which 27HC increases EV secretion, and how these EVs promote breast cancer progression. Collectively, however, our data indicate that EV secretion and content can be regulated by a cholesterol metabolite, which may have detrimental effects in terms of disease progression, important findings given the prevalence of both breast cancer and hypercholesterolemia.
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Affiliation(s)
- Amy E Baek
- Department of Molecular and Integrative Physiology, University of Illinois Urbana-Champaign, Urbana, IL 61801, USA
- Current Affiliation: A. E. Baek’s current affiliation is of Bioengineering, University of Illinois Urbana-Champaign, Urbana, IL 61801, USA
| | - Natalia Krawczynska
- Department of Molecular and Integrative Physiology, University of Illinois Urbana-Champaign, Urbana, IL 61801, USA
| | - Anasuya Das Gupta
- Department of Molecular and Integrative Physiology, University of Illinois Urbana-Champaign, Urbana, IL 61801, USA
| | | | - Sixian You
- Department of Bioengineering, University of Illinois Urbana-Champaign, Urbana, IL 61801, USA
- The Beckman Institute for Advanced Science and Technology, University of Illinois Urbana-Champaign, Urbana, IL 61801, USA
| | - Jaena Park
- Department of Bioengineering, University of Illinois Urbana-Champaign, Urbana, IL 61801, USA
- The Beckman Institute for Advanced Science and Technology, University of Illinois Urbana-Champaign, Urbana, IL 61801, USA
| | - Yu-Heng Deng
- Department of Chemical and Biomolecular Engineering, University of Illinois Urbana-Champaign, Urbana, IL 61801, USA
| | - Janet E Sorrells
- Department of Bioengineering, University of Illinois Urbana-Champaign, Urbana, IL 61801, USA
- The Beckman Institute for Advanced Science and Technology, University of Illinois Urbana-Champaign, Urbana, IL 61801, USA
| | - Brandi Patrice Smith
- Department of Food Science and Human Nutrition, University of Illinois Urbana-Champaign, Urbana, IL 61801, USA
| | - Liqian Ma
- Department of Molecular and Integrative Physiology, University of Illinois Urbana-Champaign, Urbana, IL 61801, USA
| | - Adam T Nelson
- Department of Molecular and Integrative Physiology, University of Illinois Urbana-Champaign, Urbana, IL 61801, USA
| | - Hannah B McDowell
- Department of Molecular and Integrative Physiology, University of Illinois Urbana-Champaign, Urbana, IL 61801, USA
| | - Ashabari Sprenger
- Department of Molecular and Integrative Physiology, University of Illinois Urbana-Champaign, Urbana, IL 61801, USA
| | - Madeline A Henn
- Department of Molecular and Integrative Physiology, University of Illinois Urbana-Champaign, Urbana, IL 61801, USA
| | - Zeynep Madak-Erdogan
- Department of Food Science and Human Nutrition, University of Illinois Urbana-Champaign, Urbana, IL 61801, USA
- Cancer Center at Illinois, University of Illinois Urbana-Champaign, Urbana, IL 61801, United States
- Division of Nutritional Sciences, University of Illinois Urbana-Champaign, Urbana, IL 61801, USA
| | - Hyunjoon Kong
- Department of Chemical and Biomolecular Engineering, University of Illinois Urbana-Champaign, Urbana, IL 61801, USA
- Cancer Center at Illinois, University of Illinois Urbana-Champaign, Urbana, IL 61801, United States
- Carle Illinois College of Medicine, University of Illinois Urbana-Champaign, Urbana, IL 61801, USA
| | - Stephen A Boppart
- Department of Bioengineering, University of Illinois Urbana-Champaign, Urbana, IL 61801, USA
- Department of Electrical and Computer Engineering, University of Illinois Urbana-Champaign, Urbana, IL 61801, USA
- The Beckman Institute for Advanced Science and Technology, University of Illinois Urbana-Champaign, Urbana, IL 61801, USA
- Cancer Center at Illinois, University of Illinois Urbana-Champaign, Urbana, IL 61801, United States
- University of Illinois Cancer Center, University of Illinois at Chicago, Chicago, IL 61801, USA
- Carle Illinois College of Medicine, University of Illinois Urbana-Champaign, Urbana, IL 61801, USA
| | - Marni D Boppart
- Department of Kinesiology and Community Health, University of Illinois Urbana-Champaign, Urbana, IL 61801, USA
- The Beckman Institute for Advanced Science and Technology, University of Illinois Urbana-Champaign, Urbana, IL 61801, USA
- Carle Illinois College of Medicine, University of Illinois Urbana-Champaign, Urbana, IL 61801, USA
| | - Erik R Nelson
- Department of Molecular and Integrative Physiology, University of Illinois Urbana-Champaign, Urbana, IL 61801, USA
- Cancer Center at Illinois, University of Illinois Urbana-Champaign, Urbana, IL 61801, United States
- Division of Nutritional Sciences, University of Illinois Urbana-Champaign, Urbana, IL 61801, USA
- University of Illinois Cancer Center, University of Illinois at Chicago, Chicago, IL 61801, USA
- Carl R. Woese Institute for Genomic Biology, Anticancer Discovery from Pets to People Theme, University of Illinois Urbana-Champaign, Urbana, IL 61801, USA
- Correspondence: Erik R. Nelson, University of Illinois at Urbana-Champaign, 407 S Goodwin Ave (MC-114), Urbana, IL 61801, USA. E-mail:
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Malek M, Dana N, Ghasemi A, Ghasemi M. The antagonistic atorvastatin-glibenclamide interactions suppressed the atorvastatin-induced Bax/cytochrome c/p53 mRNA expressions and increased Rho A mRNA expression in B16f10 melanoma cell culture. GENE REPORTS 2021. [DOI: 10.1016/j.genrep.2021.101156] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/21/2022]
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Hosio M, Urpilainen E, Hautakoski A, Marttila M, Arffman M, Sund R, Ahtikoski A, Puistola U, Läärä E, Karihtala P, Jukkola A. Association of antidiabetic medication and statins with survival from ductal and lobular breast carcinoma in women with type 2 diabetes. Sci Rep 2021; 11:10445. [PMID: 34001921 PMCID: PMC8129135 DOI: 10.1038/s41598-021-88488-x] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2021] [Accepted: 04/06/2021] [Indexed: 12/22/2022] Open
Abstract
We investigated the survival of female patients with pre-existing type 2 diabetes (T2D) diagnosed with invasive ductal carcinoma (IDC) and invasive lobular carcinoma (ILC) of breast, in relation to the use of metformin, other antidiabetic medication (ADM) and statins. The study cohort consisted of 3,165 women (2,604 with IDC and 561 with ILC). The cumulative mortality from breast cancer (BC) and from other causes was calculated using the Aalen-Johansen estimator. The cause-specific mortality rates were analysed by Cox models, and adjusted hazard ratios (HRs) were estimated for the use of different medications. No evidence of an association of metformin use with BC mortality was observed in either IDC (HR 0.92, 95% confidence interval [CI] 0.64-1.31) or ILC (HR 0.68, 95% CI 0.32-1.46) patients, when compared to other oral ADMs. The mortality from other causes was found to be lower amongst the IDC patients using metformin (HR 0.64, 95% CI 0.45-0.89), but amongst ILC patients the evidence was inconclusive (HR 1.22, 95% CI 0.64-2.32). Statin use was consistently associated with reduced mortality from BC in IDC patients (HR 0.77, 95% CI 0.62-0.96) and ILC patients (HR 0.59, 95% CI 0.37-0.96), and also mortality from other causes in IDC patients (HR 0.81, 95% CI 0.67-0.96) and in ILC patients (HR 0.66, 95% CI 0.43-1.01). We found no sufficient evidence for the possible effects of metformin and statins on the prognosis of BC being different in the two histological subtypes.
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MESH Headings
- Adult
- Aged
- Aged, 80 and over
- Breast Neoplasms/complications
- Breast Neoplasms/mortality
- Breast Neoplasms/therapy
- Carcinoma, Ductal, Breast/complications
- Carcinoma, Ductal, Breast/mortality
- Carcinoma, Ductal, Breast/therapy
- Carcinoma, Lobular/complications
- Carcinoma, Lobular/mortality
- Carcinoma, Lobular/therapy
- Diabetes Mellitus, Type 2/complications
- Diabetes Mellitus, Type 2/drug therapy
- Female
- Follow-Up Studies
- Humans
- Hydroxymethylglutaryl-CoA Reductase Inhibitors/therapeutic use
- Hypoglycemic Agents/therapeutic use
- Middle Aged
- Prognosis
- Registries/statistics & numerical data
- Survival Analysis
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Affiliation(s)
- Mayu Hosio
- Department of Oncology and Radiotherapy, Medical Research Center Oulu, Oulu University Hospital and University of Oulu, PO Box 22, 90029, Oulu, Finland.
| | - Elina Urpilainen
- Department of Obstetrics and Gynaecology, PEDEGO Research Unit, Medical Research Center Oulu, Oulu University Hospital and University of Oulu, PO Box 23, 90029, Oulu, Finland
| | - Ari Hautakoski
- Research Unit of Mathematical Sciences, University of Oulu, PO Box 3000, 90014, Oulu, Finland
| | - Mikko Marttila
- Orion Corporation, Orionintie 1, PO Box 65, 02101, Espoo, Finland
| | - Martti Arffman
- Service System Research Unit, Finnish Institute for Health and Welfare, PO Box 30, 00271, Helsinki, Finland
| | - Reijo Sund
- Institute of Clinical Medicine, University of Eastern Finland, PO Box 1627, 70211, Kuopio, Finland
| | - Anne Ahtikoski
- Cancer and Translational Medicine Research Unit, Department of Pathology, Oulu University Hospital and University of Oulu, PO Box 50, 90029, Oulu, Finland
| | - Ulla Puistola
- Department of Obstetrics and Gynaecology, PEDEGO Research Unit, Medical Research Center Oulu, Oulu University Hospital and University of Oulu, PO Box 23, 90029, Oulu, Finland
| | - Esa Läärä
- Research Unit of Mathematical Sciences, University of Oulu, PO Box 3000, 90014, Oulu, Finland
| | - Peeter Karihtala
- Department of Oncology and Radiotherapy, Medical Research Center Oulu, Oulu University Hospital and University of Oulu, PO Box 22, 90029, Oulu, Finland
- Department of Oncology, Helsinki University Comprehensive Cancer Center, P.O.Box 180, 00029, Helsinki, Finland
- University of Helsinki, Helsinki, Finland
| | - Arja Jukkola
- Department of Oncology and Radiotherapy, Cancer Center Tampere, Tampere University Hospital, Tampere, Finland
- Faculty of Medicine and Health Technology, Tampere University, Box 2000, 33521, Tampere, Finland
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Xu WH, Zhou YH. The relationship between post-diagnostic statin usage and breast cancer prognosis varies by hormone receptor phenotype: a systemic review and meta-analysis. Arch Gynecol Obstet 2021; 304:1315-1321. [PMID: 33891208 DOI: 10.1007/s00404-021-06065-z] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2020] [Accepted: 04/09/2021] [Indexed: 12/24/2022]
Abstract
BACKGROUND Preclinical studies and epidemiologic data had indicated statins had antineoplastic properties in breast cancer patients. Since breast cancer treatment is based on its phenotype, it is important to explore influence of post-diagnosis statin usage on breast cancer patients with different phenotypes. METHODS We searched the related studies between inception and August, 2019 from MEDLINE and EMBASE. A total of 7 studies with 24,541 patients were identified. Stata/SE 15.0 and Review Manager 5.3 were used to analyze data. Inconsistency index was used to estimate heterogeneity. Begg's and Egger's regression test was used to examine publication bias. RESULTS Overall post-diagnostic statin use was associated with improved recurrence free survival (recurrence free survival (RFS); hazard ratio (HR) 0.74; 95% confidential interval (95% CI) 0.57-0.98), overall survival (overall survival (OS); HR 0.53; 95% CI 0.31-0.91) and cancer-specific survival (cancer-specific survival (CSS); and HR 0.61; 95% CI 0.41-0.91). In hormone receptor positive patients, statin use was associated with improved CSS (HR 0.74, 95% CI 0.65-0.84). No protective effect was found in either OS or RFS. In hormone receptor negative patients, statin was associated with reduced OS (HR 2.19, 95% CI 1.34-3.59) and reduced RFS, but without statistical significance. CONCLUSIONS Post-diagnostic statin use was associated with improved RFS, OS and CSS in breast cancer patients. Subgroup analysis indicted that the benefits of statin usage varied from hormone receptor phenotype type. Prospective randomized trial with patients of different hormone receptor types might be needed to help identify which subtype of breast cancer patients would benefit from post-diagnostic statin usage.
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Affiliation(s)
- Wen-Huan Xu
- Department of Medical Oncology, The Affiliated Hospital of Jiangnan University, Wuxi, China
| | - Yun-Hai Zhou
- Department of General Surgery, The Affiliated Wuxi No.2 People's Hospital of Nanjing Medical University, Wuxi, 214002, China.
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H. Alkhatib M, M. Alkreathy H, I. Al Omar M, S. Balamash K, Abdu 4 F, Esmat A. Doxorubicin supplemented with pravastatin in lipid nanoemulsion induces antineoplastic activity with limited hepatotoxicity and cardiotoxicity in tumor-bearing mice. ASIAN JOURNAL OF PHARMACEUTICAL RESEARCH AND HEALTH CARE 2021. [DOI: 10.18311/ajprhc/2021/26066] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022]
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Chen C, Wu H, Kong D, Xu Y, Zhang Z, Chen F, Zou L, Li Z, Shui J, Luo H, Liu SH, Yu J, Wang K, Brunicardi FC. Transcriptome sequencing analysis reveals unique and shared antitumor effects of three statins in pancreatic cancer. Oncol Rep 2020; 44:2569-2580. [PMID: 33125137 PMCID: PMC7640361 DOI: 10.3892/or.2020.7810] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2020] [Accepted: 09/15/2020] [Indexed: 12/20/2022] Open
Abstract
Statins, a class of commonly prescribed cholesterol‑lowering medications, have been revealed to influence the risk of multiple types of cancer. However, the antitumor effects of statins on pancreatic cancer and their differential efficacy among a variety of statins are not currently well‑defined. The aim of the present study was therefore to identify and compare the genes and related biological pathways that were affected by each individual statin on pancreatic cancer. Two human pancreatic cancer cell lines, MiaPaCa2 and PANC1, were exposed to three statins, lovastatin, fluvastatin and simvastatin. The inhibitory effect of statins on pancreatic cancer cell proliferation was first validated. Next, RNA‑seq analysis was used to determine the gene expression alterations in either low (2 µM) or high (20 µM) statin concentration‑treated cancer cells. Marked differences in gene transcription profiles of both pancreatic cancer cell lines exposed to high concentration statins were observed. Notably, the high concentration statins significantly suppressed core‑gene CCNA2‑associated cell cycle and DNA replication pathways and upregulated genes involved in ribosome and autophagy pathways. However, the low concentration statin‑induced gene expression alterations were only detected in MiaPaCa2 cells. In conclusion, a marked difference in the intra and inter cell‑type performance of pancreatic cancer cells exposed to a variety of statins at low or high concentrations was reported herein, which may provide insights for the potential clinical use of statins in future pancreatic cancer therapeutics.
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Affiliation(s)
- Cheng Chen
- The NHC Key Laboratory of Drug Addiction Medicine, The First Affiliated Hospital of Kunming Medical University, Kunming, Yunnan 650032, P.R. China
- Yunnan Institute of Digestive Disease, The First Affiliated Hospital of Kunming Medical University, Kunming, Yunnan 650032, P.R. China
| | - Hongjin Wu
- The NHC Key Laboratory of Drug Addiction Medicine, The First Affiliated Hospital of Kunming Medical University, Kunming, Yunnan 650032, P.R. China
- Yunnan Institute of Digestive Disease, The First Affiliated Hospital of Kunming Medical University, Kunming, Yunnan 650032, P.R. China
| | - Deshengyue Kong
- Yunnan Institute of Digestive Disease, The First Affiliated Hospital of Kunming Medical University, Kunming, Yunnan 650032, P.R. China
| | - Yu Xu
- The NHC Key Laboratory of Drug Addiction Medicine, The First Affiliated Hospital of Kunming Medical University, Kunming, Yunnan 650032, P.R. China
- Yunnan Institute of Digestive Disease, The First Affiliated Hospital of Kunming Medical University, Kunming, Yunnan 650032, P.R. China
| | - Zunyue Zhang
- The NHC Key Laboratory of Drug Addiction Medicine, The First Affiliated Hospital of Kunming Medical University, Kunming, Yunnan 650032, P.R. China
- Yunnan Institute of Digestive Disease, The First Affiliated Hospital of Kunming Medical University, Kunming, Yunnan 650032, P.R. China
| | - Fengrong Chen
- The NHC Key Laboratory of Drug Addiction Medicine, The First Affiliated Hospital of Kunming Medical University, Kunming, Yunnan 650032, P.R. China
- Yunnan Institute of Digestive Disease, The First Affiliated Hospital of Kunming Medical University, Kunming, Yunnan 650032, P.R. China
| | - Lei Zou
- The NHC Key Laboratory of Drug Addiction Medicine, The First Affiliated Hospital of Kunming Medical University, Kunming, Yunnan 650032, P.R. China
- Yunnan Institute of Digestive Disease, The First Affiliated Hospital of Kunming Medical University, Kunming, Yunnan 650032, P.R. China
| | - Ziwei Li
- Shanghai International Travel Healthcare Center, Shanghai 200000, P.R. China
| | - Jin Shui
- Shanghai International Travel Healthcare Center, Shanghai 200000, P.R. China
| | - Huayou Luo
- Yunnan Institute of Digestive Disease, The First Affiliated Hospital of Kunming Medical University, Kunming, Yunnan 650032, P.R. China
| | - Shi-He Liu
- Department of Surgery, College of Medicine and Life Sciences, University of Toledo, Toledo, OH 43614, USA
| | - Juehua Yu
- The NHC Key Laboratory of Drug Addiction Medicine, The First Affiliated Hospital of Kunming Medical University, Kunming, Yunnan 650032, P.R. China
- Yunnan Institute of Digestive Disease, The First Affiliated Hospital of Kunming Medical University, Kunming, Yunnan 650032, P.R. China
- Department of Surgery, College of Medicine and Life Sciences, University of Toledo, Toledo, OH 43614, USA
| | - Kunhua Wang
- The NHC Key Laboratory of Drug Addiction Medicine, The First Affiliated Hospital of Kunming Medical University, Kunming, Yunnan 650032, P.R. China
- Yunnan Institute of Digestive Disease, The First Affiliated Hospital of Kunming Medical University, Kunming, Yunnan 650032, P.R. China
| | - F. Charles Brunicardi
- Department of Surgery, College of Medicine and Life Sciences, University of Toledo, Toledo, OH 43614, USA
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Revilla G, Cedó L, Tondo M, Moral A, Pérez JI, Corcoy R, Lerma E, Fuste V, Reddy ST, Blanco-Vaca F, Mato E, Escolà-Gil JC. LDL, HDL and endocrine-related cancer: From pathogenic mechanisms to therapies. Semin Cancer Biol 2020; 73:134-157. [PMID: 33249202 DOI: 10.1016/j.semcancer.2020.11.012] [Citation(s) in RCA: 39] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2020] [Revised: 10/19/2020] [Accepted: 11/16/2020] [Indexed: 02/07/2023]
Abstract
Cholesterol is essential for a variety of functions in endocrine-related cells, including hormone and steroid production. We have reviewed the progress to date in research on the role of the main cholesterol-containing lipoproteins; low-density lipoprotein (LDL) and high-density lipoprotein (HDL), and their impact on intracellular cholesterol homeostasis and carcinogenic pathways in endocrine-related cancers. Neither LDL-cholesterol (LDL-C) nor HDL-cholesterol (HDL-C) was consistently associated with endocrine-related cancer risk. However, preclinical studies showed that LDL receptor plays a critical role in endocrine-related tumor cells, mainly by enhancing circulating LDL-C uptake and modulating tumorigenic signaling pathways. Although scavenger receptor type BI-mediated uptake of HDL could enhance cell proliferation in breast, prostate, and ovarian cancer, these effects may be counteracted by the antioxidant and anti-inflammatory properties of HDL. Moreover, 27-hydroxycholesterol a metabolite of cholesterol promotes tumorigenic processes in breast and epithelial thyroid cancer. Furthermore, statins have been reported to reduce the incidence of breast, prostate, pancreatic, and ovarian cancer in large clinical trials, in part because of their ability to lower cholesterol synthesis. Overall, cholesterol homeostasis deregulation in endocrine-related cancers offers new therapeutic opportunities, but more mechanistic studies are needed to translate the preclinical findings into clinical therapies.
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Affiliation(s)
- Giovanna Revilla
- Institut de Recerca de l'Hospital de la Santa Creu i Sant Pau, Institut d'Investigacions Biomèdiques (IIB) Sant Pau, C/ Sant Quintí 77, 08041 Barcelona Spain; Departament de Bioquímica i Biologia Molecular, Universitat Autònoma de Barcelona, C/ Antoni M. Claret 167, 08025 Barcelona, Spain
| | - Lídia Cedó
- Institut de Recerca de l'Hospital de la Santa Creu i Sant Pau, Institut d'Investigacions Biomèdiques (IIB) Sant Pau, C/ Sant Quintí 77, 08041 Barcelona Spain; CIBER de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), C/ Monforte de Lemos 3-5, 28029 Madrid, Spain
| | - Mireia Tondo
- Institut de Recerca de l'Hospital de la Santa Creu i Sant Pau, Institut d'Investigacions Biomèdiques (IIB) Sant Pau, C/ Sant Quintí 77, 08041 Barcelona Spain; Servei de Bioquímica, Hospital de la Santa Creu i Sant Pau, C/ Sant Quintí 89, 08041 Barcelona, Spain
| | - Antonio Moral
- Department of General Surgery, Hospital de la Santa Creu i Sant Pau, C/ Sant Quintí 89, 08041 Barcelona, Spain; Departament de Medicina, Universitat Autònoma de Barcelona, C/ Antoni M. Claret 167, 08025 Barcelona, Spain
| | - José Ignacio Pérez
- Department of General Surgery, Hospital de la Santa Creu i Sant Pau, C/ Sant Quintí 89, 08041 Barcelona, Spain
| | - Rosa Corcoy
- Departament de Medicina, Universitat Autònoma de Barcelona, C/ Antoni M. Claret 167, 08025 Barcelona, Spain; CIBER de Bioingeniería, Biomateriales y Nanomedicina (CIBER-BBN), C/ Monforte de Lemos 3-5, 28029 Madrid, Spain; Department of Endocrinology and Nutrition, Hospital de la Santa Creu i Sant Pau, C/ Sant Quintí 89, 08041 Barcelona, Spain
| | - Enrique Lerma
- Institut de Recerca de l'Hospital de la Santa Creu i Sant Pau, Institut d'Investigacions Biomèdiques (IIB) Sant Pau, C/ Sant Quintí 77, 08041 Barcelona Spain; Department of Anatomic Pathology, Hospital de la Santa Creu i Sant Pau, C/ Sant Quintí 89, 08041 Barcelona, Spain
| | - Victoria Fuste
- Institut de Recerca de l'Hospital de la Santa Creu i Sant Pau, Institut d'Investigacions Biomèdiques (IIB) Sant Pau, C/ Sant Quintí 77, 08041 Barcelona Spain; Department of Anatomic Pathology, Hospital de la Santa Creu i Sant Pau, C/ Sant Quintí 89, 08041 Barcelona, Spain
| | - Srivinasa T Reddy
- Department of Molecular and Medical Pharmacology, David Geffen School of Medicine, University of California, Los Angeles, CA, 90095-1736, USA
| | - Francisco Blanco-Vaca
- Institut de Recerca de l'Hospital de la Santa Creu i Sant Pau, Institut d'Investigacions Biomèdiques (IIB) Sant Pau, C/ Sant Quintí 77, 08041 Barcelona Spain; Servei de Bioquímica, Hospital de la Santa Creu i Sant Pau, C/ Sant Quintí 89, 08041 Barcelona, Spain.
| | - Eugènia Mato
- Institut de Recerca de l'Hospital de la Santa Creu i Sant Pau, Institut d'Investigacions Biomèdiques (IIB) Sant Pau, C/ Sant Quintí 77, 08041 Barcelona Spain; CIBER de Bioingeniería, Biomateriales y Nanomedicina (CIBER-BBN), C/ Monforte de Lemos 3-5, 28029 Madrid, Spain.
| | - Joan Carles Escolà-Gil
- Institut de Recerca de l'Hospital de la Santa Creu i Sant Pau, Institut d'Investigacions Biomèdiques (IIB) Sant Pau, C/ Sant Quintí 77, 08041 Barcelona Spain.
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Feldt M, Menard J, Rosendahl AH, Lettiero B, Bendahl PO, Belting M, Borgquist S. The effect of statin treatment on intratumoral cholesterol levels and LDL receptor expression: a window-of-opportunity breast cancer trial. Cancer Metab 2020; 8:25. [PMID: 33292612 PMCID: PMC7682108 DOI: 10.1186/s40170-020-00231-8] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2020] [Accepted: 10/27/2020] [Indexed: 12/23/2022] Open
Abstract
Background Deregulated lipid metabolism is common in cancer cells and the mevalonate pathway, which synthesizes cholesterol, is central in lipid metabolism. This study aimed to assess statin-induced changes of the intratumoral levels of cholesterol and the expression of the low-density lipoprotein receptor (LDLR) to enhance our understanding of the role of the mevalonate pathway in cancer cholesterol metabolism. Methods This study is based on a phase II clinical trial designed as a window-of-opportunity trial including 50 breast cancer patients treated with 80 mg of atorvastatin/day for 2 weeks, between the time of diagnosis and breast surgery. Lipids were extracted from frozen tumor tissue sampled pre- and post-atorvastatin treatment. Intratumoral cholesterol levels were measured using a fluorometric quantitation assay. LDLR expression was evaluated by immunohistochemistry on formalin-fixed paraffin-embedded tumor tissue. Paired blood samples pre- and post-atorvastatin were analyzed for circulating low-density lipoprotein (LDL), high-density lipoprotein (HDL), apolipoprotein A1, and apolipoprotein B. In vitro experiments on MCF-7 breast cancer cells treated with atorvastatin were performed for comparison on the cellular level. Results In the trial, 42 patients completed all study parts. From the paired tumor tissue samples, assessment of the cholesterol levels was achievable for 14 tumors, and for the LDLR expression in 24 tumors. Following atorvastatin treatment, the expression of LDLR was significantly increased (P = 0.004), while the intratumoral levels of total cholesterol remained stable. A positive association between intratumoral cholesterol levels and tumor proliferation measured by Ki-67 expression was found. In agreement with the clinical findings, results from in vitro experiments showed no significant changes of the intracellular cholesterol levels after atorvastatin treatment while increased expression of the LDLR was found, although not reaching statistical significance. Conclusions This study shows an upregulation of LDLR and preserved intratumoral cholesterol levels in breast cancer patients treated with statins. Together with previous findings on the anti-proliferative effect of statins in breast cancer, the present data suggest a potential role for LDLR in the statin-induced regulation of breast cancer cell proliferation. Trial registration The study has been registered at ClinicalTrials.gov (i.e., ID number: NCT00816244, NIH), December 30, 2008. Supplementary Information The online version contains supplementary material available at 10.1186/s40170-020-00231-8.
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Affiliation(s)
- Maria Feldt
- Department of Clinical Sciences Lund, Division of Oncology and Pathology, Lund University, Lund, Sweden. .,Department of Oncology, Skåne University Hospital, Lund, Sweden.
| | - Julien Menard
- Department of Clinical Sciences Lund, Division of Oncology and Pathology, Lund University, Lund, Sweden
| | - Ann H Rosendahl
- Department of Clinical Sciences Lund, Division of Oncology and Pathology, Lund University, Lund, Sweden.,Department of Oncology, Skåne University Hospital, Lund, Sweden
| | - Barbara Lettiero
- Department of Clinical Sciences Lund, Division of Oncology and Pathology, Lund University, Lund, Sweden
| | - Pär-Ola Bendahl
- Department of Clinical Sciences Lund, Division of Oncology and Pathology, Lund University, Lund, Sweden
| | - Mattias Belting
- Department of Clinical Sciences Lund, Division of Oncology and Pathology, Lund University, Lund, Sweden.,Department of Oncology, Skåne University Hospital, Lund, Sweden.,Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden
| | - Signe Borgquist
- Department of Clinical Sciences Lund, Division of Oncology and Pathology, Lund University, Lund, Sweden.,Department of Oncology, Aarhus University Hospital, Aarhus, Denmark
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Tran KB, Buchanan CM, Shepherd PR. Evolution of Molecular Targets in Melanoma Treatment. Curr Pharm Des 2020; 26:396-414. [PMID: 32000640 DOI: 10.2174/1381612826666200130091318] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2019] [Accepted: 11/21/2019] [Indexed: 12/12/2022]
Abstract
Melanoma is the deadliest type of skin cancers, accounting for more than 80% of skin cancer mortality. Although melanoma was known very early in the history of medicine, treatment for this disease had remained largely the same until very recently. Previous treatment options, including removal surgery and systemic chemotherapy, offered little benefit in extending the survival of melanoma patients. However, the last decade has seen breakthroughs in melanoma treatment, which all emerged following new insight into the oncogenic signaling of melanoma. This paper reviewed the evolution of drug targets for melanoma treatment based on the emergence of novel findings in the molecular signaling of melanoma. One of the findings that are most influential in melanoma treatment is that more than 50% of melanoma tumors contain BRAF mutations. This is fundamental for the development of BRAF inhibitors, which is the first group of drugs that significantly improves the overall survival of melanoma patients compared to the traditional chemotherapeutic dacarbazine. More recently, findings of the role of immune checkpoint molecules such as CTLA-4 and PD1/PD-L1 in melanoma biology have led to the development of a new therapeutic category: immune checkpoint inhibitors, which, for the first time in the history of cancer treatment, produced a durable response in a subset of melanoma patients. However, as this paper discussed next, there is still an unmet need for melanoma treatment. A significant population of patients did not respond to either BRAF inhibitors or immune checkpoint inhibitors. Of those patients who gained an initial response from those therapies, a remarkable percentage would develop drug resistance even when MEK inhibitors were added to the treatment. Finally, this paper discusses some possible targets for melanoma treatment.
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Affiliation(s)
- Khanh B Tran
- Department of Molecular Medicine and Pathology, University of Auckland, New Zealand.,Maurice Wilkins Centre for Molecular Biodiscovery, Auckland, New Zealand
| | - Christina M Buchanan
- Department of Molecular Medicine and Pathology, University of Auckland, New Zealand.,Maurice Wilkins Centre for Molecular Biodiscovery, Auckland, New Zealand
| | - Peter R Shepherd
- Department of Molecular Medicine and Pathology, University of Auckland, New Zealand.,Maurice Wilkins Centre for Molecular Biodiscovery, Auckland, New Zealand.,Auckland Cancer Society Research Centre, University of Auckland, New Zealand
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Use of Non-Cancer Medications in New Zealand Women at the Diagnosis of Primary Invasive Breast Cancer: Prevalence, Associated Factors and Effects on Survival. INTERNATIONAL JOURNAL OF ENVIRONMENTAL RESEARCH AND PUBLIC HEALTH 2020; 17:ijerph17217962. [PMID: 33138255 PMCID: PMC7663632 DOI: 10.3390/ijerph17217962] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/28/2020] [Revised: 10/20/2020] [Accepted: 10/26/2020] [Indexed: 11/17/2022]
Abstract
Background: Assessing the use of multiple medications in cancer patients is crucial as such use may affect cancer outcomes. This study reports the prevalence of non-cancer medication use at breast cancer diagnosis, its associated factors, and its effect on survival. Methods: We identified all women diagnosed with primary invasive breast cancer between 1 January 2007 and 31 December 2016, from four population-based breast cancer registries, in Auckland, Waikato, Wellington, and Christchurch, New Zealand. Through linkage to the pharmaceutical records, we obtained information on non-cancer medications that were dispensed for a minimum of 90 days’ supply between one year before cancer diagnosis and first cancer treatment. We performed ordered logistic regressions to identify associated factors and Cox regressions to investigate its effect on patient survival. Results: Of 14,485 patients, 52% were dispensed at least one drug (mean—1.3 drugs; maximum—13 drugs), with a higher prevalence observed in patients who were older, treated at a public facility, more economically deprived, and screen-detected. The use of 2–3 drugs showed a reduced non-breast cancer mortality (HR = 0.75, 95%CI = 0.60–0.92) in previously hospitalised patients, with other groups showing non-significant associations when adjusted for confounding factors. Drug use was not associated with changes in breast cancer-specific mortality. Conclusions: Non-cancer medication use at breast cancer diagnosis was common in New Zealand, more prevalent in older and disadvantaged women, and showed no effect on breast cancer-specific mortality, but a reduction in other cause mortality with the use of 2–3 drugs.
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Feng JL, Qin X. Does adherence to lipid-lowering medications improve cancer survival? A nationwide study of breast and colorectal cancer, and melanoma. Br J Clin Pharmacol 2020; 87:1847-1858. [PMID: 33084072 DOI: 10.1111/bcp.14573] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2020] [Revised: 09/14/2020] [Accepted: 09/17/2020] [Indexed: 12/18/2022] Open
Abstract
AIMS Inconclusive findings of lipid-lowering medications (LLMs) on cancer survival benefit require more evidence. We tested the hypothesis that adherence to this drug is associated with reduced cancer-specific mortality in a homogeneous population who had used this drug before cancer diagnosis. METHODS The Australian Cancer Database was linked to the Pharmaceutical Benefits Scheme database, and to the National Death Index (up to 2015). Medication adherence was calculated by proportion of days covered. Cox regression models with time-varying covariates were used to derive multivariable-adjusted cause-specific hazard ratio (HR) and 95% confidence interval (CI) for the associations between adherence to LLMs, statins, lipophilic, and hydrophilic statins and cancer-specific mortality. RESULTS From 2003 to 2013, 3 separate cohorts of 20 046, 11 719 and 6430 female patients with newly diagnosed breast, colorectal cancer, and melanoma respectively were identified. The 1-year adherence was similar at 1-year prediagnosis in the 3 cohorts, on average 82%. Each 10% increase in 1-year adherence to LLMs was inversely associated with cancer-specific mortality among women with breast cancer (fully adjusted HR = 0.92, 95% CI 0.91-0.93), colorectal cancer (fully adjusted HR = 0.92, 95% CI 0.91-0.93), or melanoma (fully adjusted HR = 0.97, 95% CI 0.94-1.00). The reductions in cancer-specific mortality were more pronounced for women who adhered to lipophilic than hydrophilic statins in all 3 cancers albeit not statistically significant for melanoma. CONCLUSION Among LLM users, adherence to this drug is associated with a decrease in cancer-specific mortality. If confirmed, LLMs could be considered as an adjuvant cancer therapy to improve prognosis in cancer survivors.
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Affiliation(s)
- Jia-Li Feng
- Population Health Department, QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia.,Prevention Division, Queensland Health, Brisbane, QLD, Australia
| | - Xiwen Qin
- Centre for Medicine Use and Safety (CMUS), Faculty of Pharmacy and Pharmaceutical Science, Monash University, Melbourne, VIC, Australia.,School of Population and Global Health, Faculty of Medicine, Dentistry and Health Sciences, The University of Western Australia, Perth, WA, Australia
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Lv H, Shi D, Fei M, Chen Y, Xie F, Wang Z, Wang Y, Hu P. Association Between Statin Use and Prognosis of Breast Cancer: A Meta-Analysis of Cohort Studies. Front Oncol 2020; 10:556243. [PMID: 33178584 PMCID: PMC7596255 DOI: 10.3389/fonc.2020.556243] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2020] [Accepted: 09/11/2020] [Indexed: 12/20/2022] Open
Abstract
Background: Statin, a lipid-lowering drug, has been suggested to confer anticancer efficacy. However, previous studies evaluating the association between statin use and prognosis in breast cancer showed inconsistent results. A meta-analysis was performed to evaluate the association between statin use and clinical outcome in women with breast cancer. Methods: Cohort studies comparing recurrence or disease-specific mortality in women with breast cancer with and without using of statins were identified by search of PubMed, Embase, and Cochrane's Library databases. A random-effect model, incorporating the inter-study heterogeneity, was used to combine the results. Subgroup analyses were performed to evaluate the influences of study characteristics on the outcomes Results: Seventeen cohort studies with 168,700 women with breast cancer were included. Pooled results showed that statin use was significantly associated with a lower risk of breast cancer recurrence (adjusted hazard ratio [HR] = 0.72, p < 0.001) and breast cancer mortality (HR = 0.80, p < 0.001). Subgroup analysis showed that timing of statin use, statin type, study design, sample size, or quality score did not significantly affect the outcomes. However, statin use was associated with more remarkably reduced breast cancer recurrence in studies with mean follow-up duration ≤ 5 years (HR = 0.55, p < 0.001) than that in studies of >5 years (HR = 0.83, p = 0.01). Conclusions: Statin use is associated with reduced recurrence and disease-specific mortality in women with breast cancer. These results should be validated in randomized controlled trials.
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Affiliation(s)
- Hui Lv
- Health Promotion Center, Zhejiang Provincial People's Hospital, People's Hospital of Hangzhou Medical College, Hangzhou, China
| | - Ding Shi
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China
| | - Min Fei
- Health Promotion Center, Zhejiang Provincial People's Hospital, People's Hospital of Hangzhou Medical College, Hangzhou, China
| | - Yu Chen
- Health Promotion Center, Zhejiang Provincial People's Hospital, People's Hospital of Hangzhou Medical College, Hangzhou, China
| | - Fei Xie
- Health Promotion Center, Zhejiang Provincial People's Hospital, People's Hospital of Hangzhou Medical College, Hangzhou, China
| | - Zhuoyan Wang
- Health Promotion Center, Zhejiang Provincial People's Hospital, People's Hospital of Hangzhou Medical College, Hangzhou, China
| | - Ying Wang
- Health Promotion Center, Zhejiang Provincial People's Hospital, People's Hospital of Hangzhou Medical College, Hangzhou, China
| | - Peiying Hu
- Health Promotion Center, Zhejiang Provincial People's Hospital, People's Hospital of Hangzhou Medical College, Hangzhou, China
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Hosio M, Urpilainen E, Hautakoski A, Marttila M, Arffman M, Sund R, Ahtikoski A, Puistola U, Karihtala P, Jukkola A, Läärä E. Survival after breast cancer in women with type 2 diabetes using antidiabetic medication and statins: a retrospective cohort study. Acta Oncol 2020; 59:1110-1117. [PMID: 32478629 DOI: 10.1080/0284186x.2020.1769858] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
Background: We assessed survival of breast cancer in women with type 2 diabetes (T2D) treated with metformin, other types of antidiabetic medication (ADM) and statins.Materials and Methods: The study cohort consisted of women with T2D and diagnosed with breast cancer in Finland in 1998─2011. Mortality rates from breast cancer and other causes were analysed by Cox models, and adjusted hazard ratios (HRs) with 95% confidence intervals (Cls) were estimated in relation to the use of different types of medication.Results: The final cohort consisted of 3,533 women. No clear evidence was found for breast cancer mortality being different in metformin users (HR 0.86, 95% Cl 0.63-1.17), but their other-cause mortality appeared to be lower (HR 0.73, 95% Cl 0.55-0.97) in comparison with women using other types of oral ADM. Other-cause mortality was higher among insulin users (HR 1.45, 95% Cl 1.16-1.80) compared with users of other oral ADMs, other than metformin. Prediagnostic statin use was observed to be associated with decreased mortality from both breast cancer (HR 0.76, 95% Cl 0.63-0.92) and other causes (HR 0.75, 95% Cl 0.64-0.87).Conclusions: We did not find any association between ADM use and disease-specific mortality among women with T2D diagnosed with breast cancer. However, interestingly, prediagnostic statin use was observed to predict reduced mortality from breast cancer and other causes. We hypothesise that treating treatment practices of T2D or hypercholesterolaemia of breast cancer patients might affect overall prognosis of women diagnosed with breast cancer and T2D.
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Affiliation(s)
- Mayu Hosio
- Department of Oncology and Radiotherapy, Medical Research Center Oulu, Oulu University Hospital and University of Oulu, Oulu, Finland
| | - Elina Urpilainen
- Department of Obstetrics and Gynaecology, PEDEGO Research Unit, Medical Research Center Oulu, Oulu University Hospital and University of Oulu, Oulu, Finland
| | - Ari Hautakoski
- Research Unit of Mathematical Sciences, University of Oulu, Oulu, Finland
| | | | - Martti Arffman
- Service System Research Unit, Finnish Institute for Health and Welfare, Helsinki, Finland
| | - Reijo Sund
- Institute of Clinical Medicine, University of Eastern Finland, Kuopio, Finland
| | - Anne Ahtikoski
- Cancer and Translational Medicine Research Unit, Department of Pathology, Oulu University Hospital and University of Oulu, Oulu, Finland
| | - Ulla Puistola
- Department of Obstetrics and Gynaecology, PEDEGO Research Unit, Medical Research Center Oulu, Oulu University Hospital and University of Oulu, Oulu, Finland
| | - Peeter Karihtala
- Department of Oncology and Radiotherapy, Medical Research Center Oulu, Oulu University Hospital and University of Oulu, Oulu, Finland
- Department of Oncology, University of Helsinki and Helsinki University Comprehensive Cancer Center, Helsinki, Finland
| | - Arja Jukkola
- Department of Oncology and Radiotherapy, Cancer Centre Tampere, Tampere University Hospital, Tampere, Finland
- Faculty of Medicine and Health Technology, Tampere University, Tampere, Finland
| | - Esa Läärä
- Research Unit of Mathematical Sciences, University of Oulu, Oulu, Finland
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Barbalata CI, Tefas LR, Achim M, Tomuta I, Porfire AS. Statins in risk-reduction and treatment of cancer. World J Clin Oncol 2020; 11:573-588. [PMID: 32879845 PMCID: PMC7443827 DOI: 10.5306/wjco.v11.i8.573] [Citation(s) in RCA: 63] [Impact Index Per Article: 12.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/28/2020] [Revised: 05/18/2020] [Accepted: 06/10/2020] [Indexed: 02/06/2023] Open
Abstract
Statins, which are competitive inhibitors of 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase, reduce cholesterol blood levels and the risk of developing cardiovascular diseases and their related complications. In addition to this main activity, statins show pleiotropic effects such as antioxidant, anti-inflammatory and antiproliferative properties, with applications in many pathologies. Based on their antiproliferative properties, in vitro and in vivo studies have investigated their effects on various types of cancer (i.e., breast cancer, prostate cancer, colorectal cancer, ovarian cancer, lung cancer) with different genetic and molecular characteristics. Many positive results were obtained, but they were highly dependent on the physiochemical properties of the statins, their dose and treatment period. Combined therapies of statins and cytotoxic drugs have also been tested, and synergistic or additive effects were observed. Moreover, observational studies performed on patients who used statins for different pathologies, revealed that statins reduced the risk of developing various cancers, and improved the outcomes for cancer patients. Currently, there are many ongoing clinical trials aimed at exploring the potential of statins to lower the mortality and the disease-recurrence risk. All these results are the foundation of new treatment directions in cancer therapy.
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Affiliation(s)
- Cristina I Barbalata
- Department of Pharmaceutical Technology and Biopharmaceutics, Faculty of Pharmacy, “Iuliu-Hatieganu” University of Medicine and Pharmacy, Cluj-Napoca 400012, Romania
| | - Lucia R Tefas
- Department of Pharmaceutical Technology and Biopharmaceutics, Faculty of Pharmacy, “Iuliu-Hatieganu” University of Medicine and Pharmacy, Cluj-Napoca 400012, Romania
| | - Marcela Achim
- Department of Pharmaceutical Technology and Biopharmaceutics, Faculty of Pharmacy, “Iuliu-Hatieganu” University of Medicine and Pharmacy, Cluj-Napoca 400012, Romania
| | - Ioan Tomuta
- Department of Pharmaceutical Technology and Biopharmaceutics, Faculty of Pharmacy, “Iuliu-Hatieganu” University of Medicine and Pharmacy, Cluj-Napoca 400012, Romania
| | - Alina S Porfire
- Department of Pharmaceutical Technology and Biopharmaceutics, Faculty of Pharmacy, “Iuliu-Hatieganu” University of Medicine and Pharmacy, Cluj-Napoca 400012, Romania
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Dattilo R, Mottini C, Camera E, Lamolinara A, Auslander N, Doglioni G, Muscolini M, Tang W, Planque M, Ercolani C, Buglioni S, Manni I, Trisciuoglio D, Boe A, Grande S, Luciani AM, Iezzi M, Ciliberto G, Ambs S, De Maria R, Fendt SM, Ruppin E, Cardone L. Pyrvinium Pamoate Induces Death of Triple-Negative Breast Cancer Stem-Like Cells and Reduces Metastases through Effects on Lipid Anabolism. Cancer Res 2020; 80:4087-4102. [PMID: 32718996 DOI: 10.1158/0008-5472.can-19-1184] [Citation(s) in RCA: 35] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2019] [Revised: 05/18/2020] [Accepted: 07/20/2020] [Indexed: 12/19/2022]
Abstract
Cancer stem-like cells (CSC) induce aggressive tumor phenotypes such as metastasis formation, which is associated with poor prognosis in triple-negative breast cancer (TNBC). Repurposing of FDA-approved drugs that can eradicate the CSC subcompartment in primary tumors may prevent metastatic disease, thus representing an effective strategy to improve the prognosis of TNBC. Here, we investigated spheroid-forming cells in a metastatic TNBC model. This strategy enabled us to specifically study a population of long-lived tumor cells enriched in CSCs, which show stem-like characteristics and induce metastases. To repurpose FDA-approved drugs potentially toxic for CSCs, we focused on pyrvinium pamoate (PP), an anthelmintic drug with documented anticancer activity in preclinical models. PP induced cytotoxic effects in CSCs and prevented metastasis formation. Mechanistically, the cell killing effects of PP were a result of inhibition of lipid anabolism and, more specifically, the impairment of anabolic flux from glucose to cholesterol and fatty acids. CSCs were strongly dependent upon activation of lipid biosynthetic pathways; activation of these pathways exhibited an unfavorable prognostic value in a cohort of breast cancer patients, where it predicted high probability of metastatic dissemination and tumor relapse. Overall, this work describes a new approach to target aggressive CSCs that may substantially improve clinical outcomes for patients with TNBC, who currently lack effective targeted therapeutic options. SIGNIFICANCE: These findings provide preclinical evidence that a drug repurposing approach to prevent metastatic disease in TNBC exploits lipid anabolism as a metabolic vulnerability against CSCs in primary tumors.
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Affiliation(s)
- Rosanna Dattilo
- Department of Research, Advanced Diagnostics, and Technological Innovations, IRCCS Regina Elena National Cancer Institute, Rome, Italy
| | - Carla Mottini
- Department of Research, Advanced Diagnostics, and Technological Innovations, IRCCS Regina Elena National Cancer Institute, Rome, Italy
| | - Emanuela Camera
- Laboratory of Cutaneous Physiopathology and Integrated Center for Metabolomics Research, San Gallicano Dermatological Institute (ISG)-IRCCS, Rome, Italy
| | - Alessia Lamolinara
- Department of Medicine and Aging Science, CAST, "G. D'Annunzio" University, Chieti-Pescara, Italy
| | - Noam Auslander
- Center for Cancer Research, NCI, NIH, Bethesda, Maryland
| | - Ginevra Doglioni
- Laboratory of Cellular Metabolism and Metabolic Regulation, VIB Center for Cancer Biology, VIB, Leuven, Belgium
- Laboratory of Cellular Metabolism and Metabolic Regulation, Department of Oncology, KU Leuven and Leuven Cancer Institute (LKI), Leuven, Belgium
| | | | - Wei Tang
- Laboratory of Human Carcinogenesis, Center for Cancer Research, NCI, NIH, Bethesda, Maryland
| | - Melanie Planque
- Laboratory of Cellular Metabolism and Metabolic Regulation, VIB Center for Cancer Biology, VIB, Leuven, Belgium
- Laboratory of Cellular Metabolism and Metabolic Regulation, Department of Oncology, KU Leuven and Leuven Cancer Institute (LKI), Leuven, Belgium
| | - Cristiana Ercolani
- S.C. Anatomia Patologica, IRCCS Regina Elena National Cancer Institute, Rome, Italy
| | - Simonetta Buglioni
- S.C. Anatomia Patologica, IRCCS Regina Elena National Cancer Institute, Rome, Italy
| | - Isabella Manni
- Department of Research, Advanced Diagnostics, and Technological Innovations, IRCCS Regina Elena National Cancer Institute, Rome, Italy
| | - Daniela Trisciuoglio
- Department of Research, Advanced Diagnostics, and Technological Innovations, IRCCS Regina Elena National Cancer Institute, Rome, Italy
- Institute of Molecular Biology and Pathology, CNR National Research Council, Rome, Italy
| | - Alessandra Boe
- Core Facilities, Italian National Institute of Health, Rome, Italy
| | - Sveva Grande
- Centro Nazionale per le Tecnologie Innovative in Sanità Pubblica, Istituto Superiore di Sanità, Rome, Italy
- Istituto Nazionale di Fisica Nucleare INFN Sez. di Roma, Rome, Italy
| | - Anna Maria Luciani
- Centro Nazionale per le Tecnologie Innovative in Sanità Pubblica, Istituto Superiore di Sanità, Rome, Italy
- Istituto Nazionale di Fisica Nucleare INFN Sez. di Roma, Rome, Italy
| | - Manuela Iezzi
- Department of Medicine and Aging Science, CAST, "G. D'Annunzio" University, Chieti-Pescara, Italy
| | - Gennaro Ciliberto
- Scientific Directorate, IRCCS Regina Elena National Cancer Institute, Rome, Italy
| | - Stefan Ambs
- Laboratory of Human Carcinogenesis, Center for Cancer Research, NCI, NIH, Bethesda, Maryland
| | - Ruggero De Maria
- Dipartimento di Medicina e Chirurgia traslazionale, Università Cattolica del Sacro Cuore, Rome, Italy
- Fondazione Policlinico Universitario "A. Gemelli" - IRCCS, Rome, Italy
| | - Sarah-Maria Fendt
- Laboratory of Cellular Metabolism and Metabolic Regulation, VIB Center for Cancer Biology, VIB, Leuven, Belgium
- Laboratory of Cellular Metabolism and Metabolic Regulation, Department of Oncology, KU Leuven and Leuven Cancer Institute (LKI), Leuven, Belgium
| | - Eytan Ruppin
- Center for Cancer Research, NCI, NIH, Bethesda, Maryland.
| | - Luca Cardone
- Department of Research, Advanced Diagnostics, and Technological Innovations, IRCCS Regina Elena National Cancer Institute, Rome, Italy.
- Institute of Biochemistry and Cellular Biology, CNR National Research Council, Rome, Italy
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