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Jiang R, Shen J, Wang X, Chen S, Wu S, Cai H. Association between body mass index combined with high-sensitivity C-reactive protein and the risk of postmenopausal breast cancer: A prospective cohort study. Mol Clin Oncol 2024; 21:64. [PMID: 39071977 PMCID: PMC11273258 DOI: 10.3892/mco.2024.2762] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2024] [Accepted: 06/20/2024] [Indexed: 07/30/2024] Open
Abstract
The present study aimed to assess the risk of postmenopausal breast cancer in women based on a combination of body mass index (BMI) and high-sensitivity C-reactive protein (hs-CRP) levels. A total of 20,400 participants were investigated as part of the 'Kailuan Study' clinical trial. Participants were classified into four groups based on BMI (BMI ≥24 or <24 kg/m2) and hs-CRP level (hs-CRP ≥3 or <3 mg/l). Cox proportional hazards models were used to evaluate the association between the combination of BMI and hs-CRP and the risk of postmenopausal breast cancer. A total of 19,540 participants met the inclusion criteria. The median follow-up time was 14.97 years, with a cumulative follow-up period of 283,599.43 person-years. Among the participants, 269 individuals were diagnosed with postmenopausal breast cancer. Individuals with a high BMI (BMI ≥24 kg/m2) and a high hs-CRP level (hs-CRP ≥3 mg/) had a greater risk of postmenopausal breast cancer compared with individuals with a low BMI (BMI <24 kg/m2) and a low hs-CRP level (<3 mg/l) (hazard ratio, 1.75; 95% confidence interval, 1.25-2.47). The sensitivity analysis showed findings consistent with the primary results. In conclusion, the combination of high BMI and high hs-CRP level is associated with an increased risk of postmenopausal breast cancer. The present study is part of the Kailuan Study. Trial registration number: ChiCTRTNCR11001489 (Chinese Clinical Trial Registry, https://www.chictr.org.cn/showproj.html?proj=8050). Date of registration: 19/07/2015.
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Affiliation(s)
- Runxue Jiang
- Department of Oncology Surgery, Tangshan People's Hospital, Tangshan, Hebei 063000, P.R. China
| | - Jianglun Shen
- Department of Oncology Surgery, Tangshan People's Hospital, Tangshan, Hebei 063000, P.R. China
| | - Xia Wang
- Department of Gynaecology, Tangshan Hongci Hospital, Tangshan, Hebei 063000, P.R. China
| | - Shuohua Chen
- Health Department of Kailuan (Group), Kailuan General Hospital, Tangshan, Hebei 063000, P.R. China
| | - Shouling Wu
- Health Department of Kailuan (Group), Kailuan General Hospital, Tangshan, Hebei 063000, P.R. China
| | - Haifeng Cai
- Department of Oncology Surgery, Tangshan People's Hospital, Tangshan, Hebei 063000, P.R. China
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Pacheco JHL, Elizondo G. Interplay between Estrogen, Kynurenine, and AHR Pathways: An immunosuppressive axis with therapeutic potential for breast cancer treatment. Biochem Pharmacol 2023; 217:115804. [PMID: 37716620 DOI: 10.1016/j.bcp.2023.115804] [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: 06/09/2023] [Revised: 09/11/2023] [Accepted: 09/11/2023] [Indexed: 09/18/2023]
Abstract
Breast cancer is one of the most common malignancies among women worldwide. Estrogen exposure via endogenous and exogenous sources during a lifetime, together with environmental exposure to estrogenic compounds, represent the most significant risk factor for breast cancer development. As breast tumors establish, multiple pathways are deregulated. Among them is the aryl hydrocarbon receptor (AHR) signaling pathway. AHR, a ligand-activated transcription factor associated with the metabolism of polycyclic aromatic hydrocarbons and estrogens, is overexpressed in breast cancer. Furthermore, AHR and estrogen receptor (ER) cross-talk pathways have been observed. Additionally, the Tryptophan (Trp) catabolizing enzymes indolamine-2,3-dioxygenase (IDO) and tryptophan-2,3-dioxygenase (TDO) are overexpressed in breast cancer. IDO/TDO catalyzes the formation of Kynurenine (KYN) and other tryptophan-derived metabolites, which are ligands of AHR. Once KYN activates AHR, it stimulates the expression of the IDO enzyme, increases the level of KYN, and activates non-canonical pathways to control inflammation and immunosuppression in breast tumors. The interplay between E2, AHR, and IDO/TDO/KYN pathways and their impact on the immune system represents an immunosuppressive axis on breast cancer. The potential modulation of the immunosuppressive E2-AHR-IDO/TDO/KYN axis has aroused great expectations in oncotherapy. The present article will review the mechanisms implicated in generating the immunosuppressive axis E2-AHR-IDO/TDO/KYN in breast cancer and the current state of knowledge as a potential therapeutic target.
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Affiliation(s)
| | - Guillermo Elizondo
- Departamento de Biología Celular, CINVESTAV-IPN, Av. IPN 2508, C.P. 07360 Ciudad de México, México.
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Holm JB, Rosendahl AH, Borgquist S. Local Biomarkers Involved in the Interplay between Obesity and Breast Cancer. Cancers (Basel) 2021; 13:cancers13246286. [PMID: 34944905 PMCID: PMC8699696 DOI: 10.3390/cancers13246286] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2021] [Revised: 11/30/2021] [Accepted: 12/07/2021] [Indexed: 12/14/2022] Open
Abstract
Simple Summary Breast cancer is the second most common cancer in women worldwide. The risk of developing breast cancer depends on various mechanisms, such as age, heredity, reproductive factors, physical inactivity, and obesity. Obesity increases the risk of breast cancer and worsens outcomes for breast cancer patients. The rate of obesity is increasing worldwide, stressing the need for awareness of the association between obesity and breast cancer. In this review, we outline the biomarkers—including cellular and soluble factors—in the breast, associated with obesity, that affect the risk of breast cancer and breast cancer prognosis. Through these biomarkers, we aim to better identify patients with obesity with a higher risk of breast cancer and an inferior prognosis. Abstract Obesity is associated with an increased risk of breast cancer, which is the most common cancer in women worldwide (excluding non-melanoma skin cancer). Furthermore, breast cancer patients with obesity have an impaired prognosis. Adipose tissue is abundant in the breast. Therefore, breast cancer develops in an adipose-rich environment. During obesity, changes in the local environment in the breast occur which are associated with breast cancer. A shift towards a pro-inflammatory state is seen, resulting in altered levels of cytokines and immune cells. Levels of adipokines, such as leptin, adiponectin, and resistin, are changed. Aromatase activity rises, resulting in higher levels of potent estrogen in the breast. Lastly, remodeling of the extracellular matrix takes place. In this review, we address the current knowledge on the changes in the breast adipose tissue in obesity associated with breast cancer initiation and progression. We aim to identify obesity-associated biomarkers in the breast involved in the interplay between obesity and breast cancer. Hereby, we can improve identification of women with obesity with an increased risk of breast cancer and an impaired prognosis. Studies investigating mammary adipocytes and breast adipose tissue in women with obesity versus women without obesity are, however, sparse and further research is needed.
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Affiliation(s)
- Jonas Busk Holm
- Department of Oncology, Aarhus University Hospital, Aarhus University, Palle Juul-Jensens Boulevard 99, 8200 Aarhus, Denmark
- Correspondence: (J.B.H.); (S.B.)
| | - Ann H. Rosendahl
- Department of Clinical Sciences Lund, Oncology, Lund University, Skåne University Hospital, Barngatan 4, 221 85 Lund, Sweden;
| | - Signe Borgquist
- Department of Oncology, Aarhus University Hospital, Aarhus University, Palle Juul-Jensens Boulevard 99, 8200 Aarhus, Denmark
- Department of Clinical Sciences Lund, Oncology, Lund University, Skåne University Hospital, Barngatan 4, 221 85 Lund, Sweden;
- Correspondence: (J.B.H.); (S.B.)
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Martínez-Pérez C, Kay C, Meehan J, Gray M, Dixon JM, Turnbull AK. The IL6-like Cytokine Family: Role and Biomarker Potential in Breast Cancer. J Pers Med 2021; 11:1073. [PMID: 34834425 PMCID: PMC8624266 DOI: 10.3390/jpm11111073] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2021] [Revised: 10/20/2021] [Accepted: 10/21/2021] [Indexed: 02/07/2023] Open
Abstract
IL6-like cytokines are a family of regulators with a complex, pleiotropic role in both the healthy organism, where they regulate immunity and homeostasis, and in different diseases, including cancer. Here we summarise how these cytokines exert their effect through the shared signal transducer IL6ST (gp130) and we review the extensive evidence on the role that different members of this family play in breast cancer. Additionally, we discuss how the different cytokines, their related receptors and downstream effectors, as well as specific polymorphisms in these molecules, can serve as predictive or prognostic biomarkers with the potential for clinical application in breast cancer. Lastly, we also discuss how our increasing understanding of this complex signalling axis presents promising opportunities for the development or repurposing of therapeutic strategies against cancer and, specifically, breast neoplasms.
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Affiliation(s)
- Carlos Martínez-Pérez
- Breast Cancer Now Edinburgh Research Team, MRC Institute of Genetics and Cancer, Western General Hospital, University of Edinburgh, Edinburgh EH4 2XU, UK; (C.K.); (J.M.D.); (A.K.T.)
- Translational Oncology Research Group, MRC Institute of Genetics and Cancer, Western General Hospital, University of Edinburgh, Edinburgh EH8 9YL, UK; (J.M.); (M.G.)
| | - Charlene Kay
- Breast Cancer Now Edinburgh Research Team, MRC Institute of Genetics and Cancer, Western General Hospital, University of Edinburgh, Edinburgh EH4 2XU, UK; (C.K.); (J.M.D.); (A.K.T.)
- Translational Oncology Research Group, MRC Institute of Genetics and Cancer, Western General Hospital, University of Edinburgh, Edinburgh EH8 9YL, UK; (J.M.); (M.G.)
| | - James Meehan
- Translational Oncology Research Group, MRC Institute of Genetics and Cancer, Western General Hospital, University of Edinburgh, Edinburgh EH8 9YL, UK; (J.M.); (M.G.)
| | - Mark Gray
- Translational Oncology Research Group, MRC Institute of Genetics and Cancer, Western General Hospital, University of Edinburgh, Edinburgh EH8 9YL, UK; (J.M.); (M.G.)
| | - J. Michael Dixon
- Breast Cancer Now Edinburgh Research Team, MRC Institute of Genetics and Cancer, Western General Hospital, University of Edinburgh, Edinburgh EH4 2XU, UK; (C.K.); (J.M.D.); (A.K.T.)
| | - Arran K. Turnbull
- Breast Cancer Now Edinburgh Research Team, MRC Institute of Genetics and Cancer, Western General Hospital, University of Edinburgh, Edinburgh EH4 2XU, UK; (C.K.); (J.M.D.); (A.K.T.)
- Translational Oncology Research Group, MRC Institute of Genetics and Cancer, Western General Hospital, University of Edinburgh, Edinburgh EH8 9YL, UK; (J.M.); (M.G.)
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Fernandez CJ, George AS, Subrahmanyan NA, Pappachan JM. Epidemiological link between obesity, type 2 diabetes mellitus and cancer. World J Methodol 2021; 11:23-45. [PMID: 34026577 PMCID: PMC8127420 DOI: 10.5662/wjm.v11.i3.23] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/13/2021] [Revised: 03/02/2021] [Accepted: 03/19/2021] [Indexed: 02/06/2023] Open
Abstract
There exists a complex interaction between obesity, type 2 diabetes mellitus (T2DM) and cancer, and an increase in the incidence of cancer is expected with the growing obesity-diabetes pandemic. The association of cancer with diabetes mellitus and obesity appears to be site-specific, the highest risk being for post-menopausal breast cancer, endometrial cancer, and colorectal cancer. Moreover, there is worsening of hyperglycaemia with the onset of cancer, evidencing a bi-directional link between cancer and diabetes mellitus and the need for monitoring for diabetes in cancer survivors. In this review, we look at the epidemiological evidence from observational studies and Mendelian randomization studies linking obesity, diabetes, and cancer, as well as the complex pathophysiological mechanisms involved, including insulin resistance with associated hyperinsulinaemia, the effect of chronic low-grade inflammation, and the effect of various adipokines that are associated with obesity and T2DM. Additionally, we describe the novel therapeutic strategies, based on their role on the discrete pathophysiological mechanisms involved in the tumourigenesis.
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Affiliation(s)
- Cornelius J Fernandez
- Department of Endocrinology and Metabolism, Pilgrim Hospital, United Lincolnshire Hospitals NHS Trust, Boston PE21 9QS, United Kingdom
| | - Annu Susan George
- Department of Medical Oncology, VPS Lakeshore Hospital, Cochin 682040, India
| | | | - Joseph M Pappachan
- Department of Endocrinology and Metabolism, Lancashire Teaching Hospitals NHS Trust, Preston PR2 9HT, United Kingdom
- Faculty of Science, Manchester Metropolitan University, Manchester M15 6BH, United Kingdom
- Faculty of Biology, Medicine and Health, The University of Manchester, Manchester M13 9PL, United Kingdom
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6
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Almekinders MMM, Schaapveld M, Thijssen B, Visser LL, Bismeijer T, Sanders J, Isnaldi E, Hofland I, Mertz M, Wessels LFA, Broeks A, Hooijberg E, Zwart W, Lips EH, Desmedt C, Wesseling J. Breast adipocyte size associates with ipsilateral invasive breast cancer risk after ductal carcinoma in situ. NPJ Breast Cancer 2021; 7:31. [PMID: 33753731 PMCID: PMC7985299 DOI: 10.1038/s41523-021-00232-w] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2020] [Accepted: 02/03/2021] [Indexed: 12/25/2022] Open
Abstract
Although ductal carcinoma in situ (DCIS) is a non-obligate precursor to ipsilateral invasive breast cancer (iIBC), most DCIS lesions remain indolent. Hence, overdiagnosis and overtreatment of DCIS is a major concern. There is an urgent need for prognostic markers that can distinguish harmless from potentially hazardous DCIS. We hypothesised that features of the breast adipose tissue may be associated with risk of subsequent iIBC. We performed a case-control study nested in a population-based DCIS cohort, consisting of 2658 women diagnosed with primary DCIS between 1989 and 2005, uniformly treated with breast conserving surgery (BCS) alone. We assessed breast adipose features with digital pathology (HALO®, Indica Labs) and related these to iIBC risk in 108 women that developed subsequent iIBC (cases) and 168 women who did not (controls) by conditional logistic regression, accounting for clinicopathological and immunohistochemistry variables. Large breast adipocyte size was significantly associated with iIBC risk (odds ratio (OR) 2.75, 95% confidence interval (95% CI) = 1.25-6.05). High cyclooxygenase (COX)-2 protein expression in the DCIS cells was also associated with subsequent iIBC (OR 3.70 (95% CI = 1.59-8.64). DCIS with both high COX-2 expression and large breast adipocytes was associated with a 12-fold higher risk (OR 12.0, 95% CI = 3.10-46.3, P < 0.001) for subsequent iIBC compared with women with smaller adipocyte size and low COX-2 expression. Large breast adipocytes combined with high COX-2 expression in DCIS is associated with a high risk of subsequent iIBC. Besides COX-2, adipocyte size has the potential to improve clinical management in patients diagnosed with primary DCIS.
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Affiliation(s)
- Mathilde M M Almekinders
- Division of Molecular Pathology, Netherlands Cancer Institute, Amsterdam, The Netherlands
- Department of Pathology, Antoni van Leeuwenhoek Hospital, Amsterdam, The Netherlands
| | - Michael Schaapveld
- Division of Psychosocial Research, Epidemiology and Biostatistics, Netherlands Cancer Institute, Amsterdam, The Netherlands
| | - Bram Thijssen
- Division of Molecular Carcinogenesis, Netherlands Cancer Institute, Amsterdam, The Netherlands
| | - Lindy L Visser
- Division of Molecular Pathology, Netherlands Cancer Institute, Amsterdam, The Netherlands
| | - Tycho Bismeijer
- Division of Molecular Carcinogenesis, Netherlands Cancer Institute, Amsterdam, The Netherlands
| | - Joyce Sanders
- Department of Pathology, Antoni van Leeuwenhoek Hospital, Amsterdam, The Netherlands
| | - Edoardo Isnaldi
- Laboratory for Translational Breast Cancer Research, Department of Oncology, KU Leuven, Leuven, Belgium
- Department of Internal Medicine and Medical Specialties, Università degli Studi di Genova, IT-16132, Genova, Italy
| | - Ingrid Hofland
- Core Facility Molecular Pathology and Biobanking, Netherlands Cancer Institute, Amsterdam, The Netherlands
| | - Marjolijn Mertz
- Bio-Imaging Facility, Netherlands Cancer Institute, Amsterdam, The Netherlands
| | - Lodewyk F A Wessels
- Division of Molecular Carcinogenesis, Netherlands Cancer Institute, Amsterdam, The Netherlands
- Oncode Institute, Utrecht, The Netherlands
| | - Annegien Broeks
- Core Facility Molecular Pathology and Biobanking, Netherlands Cancer Institute, Amsterdam, The Netherlands
| | - Erik Hooijberg
- Department of Pathology, Antoni van Leeuwenhoek Hospital, Amsterdam, The Netherlands
| | - Wilbert Zwart
- Oncode Institute, Utrecht, The Netherlands
- Division of Oncogenomics, Netherlands Cancer Institute, Amsterdam, The Netherlands
| | - Esther H Lips
- Division of Molecular Pathology, Netherlands Cancer Institute, Amsterdam, The Netherlands
| | - Christine Desmedt
- Laboratory for Translational Breast Cancer Research, Department of Oncology, KU Leuven, Leuven, Belgium
| | - Jelle Wesseling
- Division of Molecular Pathology, Netherlands Cancer Institute, Amsterdam, The Netherlands.
- Department of Pathology, Antoni van Leeuwenhoek Hospital, Amsterdam, The Netherlands.
- Department of Pathology, Leiden University Medical Center, Leiden, The Netherlands.
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7
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Miller B, Chalfant H, Thomas A, Wellberg E, Henson C, McNally MW, Grizzle WE, Jain A, McNally LR. Diabetes, Obesity, and Inflammation: Impact on Clinical and Radiographic Features of Breast Cancer. Int J Mol Sci 2021; 22:2757. [PMID: 33803201 PMCID: PMC7963150 DOI: 10.3390/ijms22052757] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2021] [Revised: 03/01/2021] [Accepted: 03/04/2021] [Indexed: 02/06/2023] Open
Abstract
Obesity, diabetes, and inflammation increase the risk of breast cancer, the most common malignancy in women. One of the mainstays of breast cancer treatment and improving outcomes is early detection through imaging-based screening. There may be a role for individualized imaging strategies for patients with certain co-morbidities. Herein, we review the literature regarding the accuracy of conventional imaging modalities in obese and diabetic women, the potential role of anti-inflammatory agents to improve detection, and the novel molecular imaging techniques that may have a role for breast cancer screening in these patients. We demonstrate that with conventional imaging modalities, increased sensitivity often comes with a loss of specificity, resulting in unnecessary biopsies and overtreatment. Obese women have body size limitations that impair image quality, and diabetes increases the risk for dense breast tis-sue. Increased density is known to obscure the diagnosis of cancer on routine screening mammography. Novel molecu-lar imaging agents with targets such as estrogen receptor, human epidermal growth factor receptor 2 (HER2), pyrimi-dine analogues, and ligand-targeted receptor probes, among others, have potential to reduce false positive results. They can also improve detection rates with increased resolution and inform therapeutic decision making. These emerg-ing imaging techniques promise to improve breast cancer diagnosis in obese patients with diabetes who have dense breasts, but more work is needed to validate their clinical application.
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Affiliation(s)
- Braden Miller
- Department of Surgery, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA; (B.M.); (H.C.)
| | - Hunter Chalfant
- Department of Surgery, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA; (B.M.); (H.C.)
| | - Alexandra Thomas
- Department of Internal Medicine, Wake Forest University School of Medicine, Wake Forest University, Winston-Salem, NC 27157, USA;
| | - Elizabeth Wellberg
- Department of Pathology, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73105, USA;
| | - Christina Henson
- Department of Radiation Oncology, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73105, USA;
| | | | - William E. Grizzle
- Department of Pathology, University of Alabama at Birmingham, Birmingham, AL 35294, USA;
| | - Ajay Jain
- Department of Surgery, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA; (B.M.); (H.C.)
- Stephenson Cancer Center, Oklahoma City, OK 73104, USA;
| | - Lacey R. McNally
- Department of Surgery, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA; (B.M.); (H.C.)
- Stephenson Cancer Center, Oklahoma City, OK 73104, USA;
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8
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Iron Complexes of Flavonoids-Antioxidant Capacity and Beyond. Int J Mol Sci 2021; 22:ijms22020646. [PMID: 33440733 PMCID: PMC7827006 DOI: 10.3390/ijms22020646] [Citation(s) in RCA: 67] [Impact Index Per Article: 16.8] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2020] [Revised: 12/30/2020] [Accepted: 01/02/2021] [Indexed: 02/07/2023] Open
Abstract
Flavonoids are common plant natural products able to suppress ROS-related damage and alleviate oxidative stress. One of key mechanisms, involved in this phenomenon is chelation of transition metal ions. From a physiological perspective, iron is the most significant transition metal, because of its abundance in living organisms and ubiquitous involvement in redox processes. The chemical, pharmaceutical, and biological properties of flavonoids can be significantly affected by their interaction with transition metal ions, mainly iron. In this review, we explain the interaction of various flavonoid structures with Fe(II) and Fe(III) ions and critically discuss the influence of chelated ions on the flavonoid biochemical properties. In addition, specific biological effects of their iron metallocomplexes, such as the inhibition of iron-containing enzymes, have been included in this review.
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Melatonin as an Oncostatic Molecule Based on Its Anti-Aromatase Role in Breast Cancer. Int J Mol Sci 2021; 22:ijms22010438. [PMID: 33406787 PMCID: PMC7795758 DOI: 10.3390/ijms22010438] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2020] [Revised: 12/28/2020] [Accepted: 12/30/2020] [Indexed: 12/17/2022] Open
Abstract
Breast cancer is the most common type of cancer. In the developmental stages of breast cancer, estrogens are strongly involved. As estrogen synthesis is regulated by the enzyme aromatase, targeting the activity of this enzyme represents a therapeutic option. The pineal hormone melatonin may exert a suppressive role on aromatase activity, leading to reduced estrogen biosynthesis. A melatonin-mediated decrease in the expression of aromatase promoters and associated genes would provide suitable evidence of this molecule’s efficacy as an aromatase inhibitor. Furthermore, melatonin intensifies radiation-induced anti-aromatase effects and counteracts the unwanted disadvantages of chemotherapeutic agents. In this manner, this review summarizes the inhibitory role of melatonin in aromatase action, suggesting its role as a possible oncostatic molecule in breast cancer.
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10
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Orlandella FM, De Stefano AE, Iervolino PLC, Buono P, Soricelli A, Salvatore G. Dissecting the molecular pathways involved in the effects of physical activity on breast cancers cells: A narrative review. Life Sci 2020; 265:118790. [PMID: 33220294 DOI: 10.1016/j.lfs.2020.118790] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2020] [Revised: 11/12/2020] [Accepted: 11/15/2020] [Indexed: 02/06/2023]
Abstract
Epidemiologic evidence suggests that obesity and sedentary are modifiable factors strongly associated with breast cancer risk worldwide. Since breast cancer represents the most frequent malignant neoplasm and the second cause of cancer-related deaths in women worldwide, an insight into the molecular mechanisms clarifying the effects of physical activity in breast cancer cells could have important implication for changing this cancer burden. In this narrative Review article, we summarize the current knowledge, regarding the effects of adapted physical activity program, focusing on the cellular signaling pathways activated and on the molecular markers involved in breast cancer. Regular exercise training in breast cancer patients has been shown to positively affect tumor-growth and survival rate. Indeed, emerging work demonstrates that regular exercise is able to affect multiple cancer hallmarks influencing the development and progression of cancer. In conclusion, changes in the circulating insulin, adipokines and estrogen levels, inflammation and oxidative stress could represent some of the possible biological mechanisms through which exercise may influence breast cancer development and recurrence.
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Affiliation(s)
| | - Anna Elisa De Stefano
- Dipartimento di Scienze Motorie e del Benessere, Università "Parthenope", Via Medina 40, 80133 Naples, Italy; CEINGE - Biotecnologie Avanzate S.c.a.r.l., Via Gaetano Salvatore 486, 80145 Naples, Italy
| | - Paola Lucia Chiara Iervolino
- CEINGE - Biotecnologie Avanzate S.c.a.r.l., Via Gaetano Salvatore 486, 80145 Naples, Italy; Dipartimento di Scienze Biomediche Avanzate, Università "Federico II", Via Pansini 5, 80131 Naples, Italy
| | - Pasqualina Buono
- Dipartimento di Scienze Motorie e del Benessere, Università "Parthenope", Via Medina 40, 80133 Naples, Italy; CEINGE - Biotecnologie Avanzate S.c.a.r.l., Via Gaetano Salvatore 486, 80145 Naples, Italy
| | - Andrea Soricelli
- IRCCS SDN, Via Emanuele Gianturco 113, 80143 Naples, Italy; Dipartimento di Scienze Motorie e del Benessere, Università "Parthenope", Via Medina 40, 80133 Naples, Italy
| | - Giuliana Salvatore
- IRCCS SDN, Via Emanuele Gianturco 113, 80143 Naples, Italy; Dipartimento di Scienze Motorie e del Benessere, Università "Parthenope", Via Medina 40, 80133 Naples, Italy; CEINGE - Biotecnologie Avanzate S.c.a.r.l., Via Gaetano Salvatore 486, 80145 Naples, Italy
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Chrysoeriol Prevents TNFα-Induced CYP19 Gene Expression via EGR-1 Downregulation in MCF7 Breast Cancer Cells. Int J Mol Sci 2020; 21:ijms21207523. [PMID: 33053908 PMCID: PMC7588959 DOI: 10.3390/ijms21207523] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2020] [Revised: 10/08/2020] [Accepted: 10/09/2020] [Indexed: 01/06/2023] Open
Abstract
Estrogen overproduction is closely associated with the development of estrogen receptor-positive breast cancer. Aromatase, encoded by the cytochrome P450 19 (CYP19) gene, regulates estrogen biosynthesis. This study aimed to identify active flavones that inhibit CYP19 expression and to explore the underlying mechanisms. CYP19 expression was evaluated using reverse transcription PCR, quantitative real-time PCR, and immunoblot analysis. The role of transcription factor early growth response gene 1 (EGR-1) in CYP19 expression was assessed using the short-hairpin RNA (shRNA)-mediated knockdown of EGR-1 expression in estrogen receptor-positive MCF-7 breast cancer cells. We screened 39 flavonoids containing 26 flavones and 13 flavanones using the EGR1 promoter reporter activity assay and observed that chrysoeriol exerted the highest inhibitory activity on tumor necrosis factor alpha (TNFα)-induced EGR-1 expression. We further characterized and demonstrated that chrysoeriol inhibits TNFα-induced CYP19 expression through inhibition of extracellular signal-regulated kinase 1/2 (ERK1/2)-mediated EGR-1 expression. Chrysoeriol may be beneficial as a dietary supplement for the prevention of estrogen receptor-positive breast cancer, or as a chemotherapeutic adjuvant in the treatment of this condition.
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12
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Thompson DA, Lehmler HJ, Kolpin DW, Hladik ML, Vargo JD, Schilling KE, LeFevre GH, Peeples TL, Poch MC, LaDuca LE, Cwiertny DM, Field RW. A critical review on the potential impacts of neonicotinoid insecticide use: current knowledge of environmental fate, toxicity, and implications for human health. ENVIRONMENTAL SCIENCE. PROCESSES & IMPACTS 2020; 22:1315-1346. [PMID: 32267911 PMCID: PMC11755762 DOI: 10.1039/c9em00586b] [Citation(s) in RCA: 193] [Impact Index Per Article: 38.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/14/2023]
Abstract
Neonicotinoid insecticides are widely used in both urban and agricultural settings around the world. Historically, neonicotinoid insecticides have been viewed as ideal replacements for more toxic compounds, like organophosphates, due in part to their perceived limited potential to affect the environment and human health. This critical review investigates the environmental fate and toxicity of neonicotinoids and their metabolites and the potential risks associated with exposure. Neonicotinoids are found to be ubiquitous in the environment, drinking water, and food, with low-level exposure commonly documented below acceptable daily intake standards. Available toxicological data from animal studies indicate possible genotoxicity, cytotoxicity, impaired immune function, and reduced growth and reproductive success at low concentrations, while limited data from ecological or cross-sectional epidemiological studies have identified acute and chronic health effects ranging from acute respiratory, cardiovascular, and neurological symptoms to oxidative genetic damage and birth defects. Due to the heavy use of neonicotinoids and potential for cumulative chronic exposure, these insecticides represent novel risks and necessitate further study to fully understand their risks to humans.
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Affiliation(s)
- Darrin A Thompson
- University of Iowa, College of Public Health, Iowa City, IA, USA. and University of Iowa, Center for Health Effects of Environmental Contamination, Iowa City, IA, USA
| | | | - Dana W Kolpin
- U.S. Geological Survey, Central Midwest Water Science Center, Iowa City, IA, USA
| | - Michelle L Hladik
- U.S. Geological Survey, California Water Science Center, Sacramento, CA, USA
| | - John D Vargo
- State Hygienic Laboratory at the University of Iowa, Iowa City, IA, USA
| | | | - Gregory H LeFevre
- University of Iowa, Department of Civil & Environmental Engineering, Iowa City, IA, USA
| | - Tonya L Peeples
- Department of Chemical Engineering, University Park, PA, USA
| | - Matthew C Poch
- University of Iowa, College of Public Health, Iowa City, IA, USA.
| | - Lauren E LaDuca
- University of Iowa, College of Public Health, Iowa City, IA, USA.
| | - David M Cwiertny
- University of Iowa, Center for Health Effects of Environmental Contamination, Iowa City, IA, USA and University of Iowa, Department of Civil & Environmental Engineering, Iowa City, IA, USA
| | - R William Field
- University of Iowa, College of Public Health, Iowa City, IA, USA.
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13
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Kumar RG, DiSanto D, Awan N, Vaughan LE, Levochkina MS, Weppner JL, Wright DW, Berga SL, Conley YP, Brooks MM, Wagner AK. Temporal Acute Serum Estradiol and Tumor Necrosis Factor-α Associations and Risk of Death after Severe Traumatic Brain Injury. J Neurotrauma 2020; 37:2198-2210. [PMID: 32375598 DOI: 10.1089/neu.2019.6577] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022] Open
Abstract
Severe traumatic brain injury (TBI) activates a robust systemic response that involves inflammatory and other factors, including estradiol (E2), associated with increased deaths. Tumor necrosis factor-alpha (TNFα) is a significant mediator of systemic shock, and it is an extra-gonadal transcription factor for E2 production. The study objectives were to test the hypotheses: (1) a positive feedback relationship exists between acute serum TNFα and E2; and (2) acute concentrations of E2 and TNFα are prognostic indicators of death after severe TBI. This prospective cohort study included N = 157 adults with severe TBI. Serum samples were collected for the first five days post-injury. The TNFα and E2 levels were averaged into two time epochs: first 72 h (T1) and second 72 h post-injury (T2). A cross-lag panel analysis conducted between T1 and T2 TNFα and E2 levels showed significant cross-lag effects: T1 TNFα and T1 E2 were related to T2 E2 and T2 TNFα, respectively. Cox proportional hazards multi variable regression models determined that increases in T1 E2 (hazard ratio [HR] = 1.79, 95% confidence interval [CI]: 1.15, 2.81), but not T2 E2 (HR = 0.91, 95% CI: 0.56, 1.47), were associated with increased risk of death. Increased T2 TNFα (HR = 2.47, 95% CI: 1.35, 4.53), and T1 TNFα (HR = 1.47, 95% CI: 0.99, 2.19), to a lesser degree, were associated with increased risk of death. Relationships of death with T2 TNFα and T1 E2 were mediated partially by cardiovascular, hepatic, and renal dysfunction. Both E2 and TNFα are systemic, reciprocally related biomarkers that may be indicative of systemic compromise and increased risk of death after severe TBI.
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Affiliation(s)
- Raj G Kumar
- Department of Physical Medicine and Rehabilitation, University of Pittsburgh, Pittsburgh, Pennsylvania.,Department of Epidemiology, University of Pittsburgh, Pittsburgh, Pennsylvania
| | - Dominic DiSanto
- Department of Physical Medicine and Rehabilitation, University of Pittsburgh, Pittsburgh, Pennsylvania
| | - Nabil Awan
- Department of Biostatistics, University of Pittsburgh, Pittsburgh, Pennsylvania
| | - Leah E Vaughan
- Department of Physical Medicine and Rehabilitation, University of Pittsburgh, Pittsburgh, Pennsylvania
| | - Marina S Levochkina
- Department of Physical Medicine and Rehabilitation, University of Pittsburgh, Pittsburgh, Pennsylvania
| | - Justin L Weppner
- Department of Physical Medicine and Rehabilitation, University of Pittsburgh, Pittsburgh, Pennsylvania
| | - David W Wright
- Department of Emergency Medicine, Emory University, Atlanta, Georgia
| | - Sarah L Berga
- Department of Reproductive Endocrinology, University of Utah, Salt Lake City, Utah
| | - Yvette P Conley
- School of Nursing, University of Pittsburgh, Pittsburgh, Pennsylvania
| | - Maria M Brooks
- Department of Epidemiology, University of Pittsburgh, Pittsburgh, Pennsylvania
| | - Amy K Wagner
- Department of Physical Medicine and Rehabilitation, University of Pittsburgh, Pittsburgh, Pennsylvania.,Center for Neuroscience, University of Pittsburgh, Pittsburgh, Pennsylvania.,Safar Center for Resuscitation Research, University of Pittsburgh, Pittsburgh, Pennsylvania
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14
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Saldanha CJ. Estrogen as a Neuroprotectant in Both Sexes: Stories From the Bird Brain. Front Neurol 2020; 11:497. [PMID: 32655477 PMCID: PMC7324752 DOI: 10.3389/fneur.2020.00497] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2020] [Accepted: 05/06/2020] [Indexed: 12/18/2022] Open
Abstract
Estrogens such as estradiol (E2) are potent effectors of neural structure and function via peripheral and central synthesis. In the zebra finch (Taeniopygia guttata), neural E2 synthesis is among the highest reported in homeotherms due to the abundant constitutive expression of aromatase (E-synthase) in discrete neuronal pools across the forebrain. Following penetrating or concussive trauma, E2 synthesis increases even further via the induced expression of aromatase in reactive astrocytes around the site of damage. Injury-associated astrocytic aromatization occurs in the brains of both sexes regardless of the site of injury and can remain elevated for weeks following trauma. Interestingly, penetrating injury induces astrocytic aromatase more rapidly in females compared to males, but this sex difference is not detectable 24 h posttrauma. Indeed, unilateral penetrating injury can increase E2 content 4-fold relative to the contralateral uninjured hemisphere, suggesting that glial aromatization may be a powerful source of neural E2 available to circuits. Glial aromatization is neuroprotective as inhibition of injury-induced aromatase increases neuroinflammation, gliosis, necrosis, apoptosis, and infarct size. These effects are ameliorated upon replacement with E2, suggesting that the songbird may have evolved a rapidly responsive neurosteroidogenic system to protect vulnerable brain circuits. The precise signals that induce aromatase expression in astrocytes include elements of the inflammatory cascade and underscore the sentinel role of the innate immune system as a crucial effector of trauma-associated E2 provision in the vertebrate brain. This review will describe the inductive signals of astroglial aromatase and the neuroprotective role for glial E2 synthesis in the adult songbird brains of both sexes.
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Affiliation(s)
- Colin J Saldanha
- Departments of Neuroscience, Biology, Psychology & The Center for Behavioral Neuroscience, American University, Washington, DC, United States
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15
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Hillers-Ziemer LE, Arendt LM. Weighing the Risk: effects of Obesity on the Mammary Gland and Breast Cancer Risk. J Mammary Gland Biol Neoplasia 2020; 25:115-131. [PMID: 32519090 PMCID: PMC7933979 DOI: 10.1007/s10911-020-09452-5] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/16/2020] [Revised: 06/02/2020] [Accepted: 06/03/2020] [Indexed: 12/17/2022] Open
Abstract
Obesity is a preventable risk factor for breast cancer following menopause. Regardless of menopausal status, obese women who develop breast cancer have a worsened prognosis. Breast tissue is comprised of mammary epithelial cells organized into ducts and lobules and surrounded by adipose-rich connective tissue. Studies utilizing multiple in vivo models of obesity as well as human breast tissue have contributed to our understanding of how obesity alters mammary tissue. Localized changes in mammary epithelial cell populations, elevated secretion of adipokines and angiogenic mediators, inflammation within mammary adipose tissue, and remodeling of the extracellular matrix may result in an environment conducive to breast cancer growth. Despite these significant alterations caused by obesity within breast tissue, studies have suggested that some, but not all, obesity-induced changes may be mitigated with weight loss. Here, we review our current understanding regarding the impact of obesity on the breast microenvironment, how obesity-induced changes may contribute to breast tumor progression, and the impact of weight loss on the breast microenvironment.
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Affiliation(s)
- Lauren E Hillers-Ziemer
- Program in Cellular and Molecular Biology, University of Wisconsin-Madison, 1525 Linden Drive, Madison, WI, 53706, USA
| | - Lisa M Arendt
- Program in Cellular and Molecular Biology, University of Wisconsin-Madison, 1525 Linden Drive, Madison, WI, 53706, USA.
- Department of Comparative Biosciences, School of Veterinary Medicine, University of Wisconsin-Madison, 2015 Linden Drive, Madison, WI, 53706, USA.
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16
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Somasundaram A, Rothenberger NJ, Stabile LP. The Impact of Estrogen in the Tumor Microenvironment. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2020; 1277:33-52. [PMID: 33119863 DOI: 10.1007/978-3-030-50224-9_2] [Citation(s) in RCA: 26] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Tumor immune escape is now a hallmark of cancer development, and therapies targeting these pathways have emerged as standard of care. Specifically, immune checkpoint signal blockade offers durable responses and increased overall survival. However, the majority of cancer patients still do not respond to checkpoint blockade immune therapy leading to an unmet need in tumor immunology research. Sex-based differences have been noted in the use of cancer immunotherapy suggesting that sex hormones such as estrogen may play an important role in tumor immune regulation. Estrogen signaling already has a known role in autoimmunity, and the estrogen receptor can be expressed across multiple immune cell populations and effect their regulation. While it has been well established that tumor cells such as ovarian carcinoma, breast carcinoma, and even lung carcinoma can be regulated by estrogen, research into the role of estrogen in the regulation of tumor-associated immune cells is still emerging. In this chapter, we discuss the role of estrogen in the tumor immune microenvironment and the possible immunotherapeutic implications of targeting estrogen in cancer patients.
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Affiliation(s)
- Ashwin Somasundaram
- Department of Medicine, Division of Hematology/Oncology, University of Pittsburgh, Pittsburgh, PA, USA.,Department of Immunology, University of Pittsburgh, Pittsburgh, PA, USA.,UPMC Hillman Cancer Center, Pittsburgh, PA, USA
| | - Natalie J Rothenberger
- Department of Medicine, Division of Hematology/Oncology, University of Pittsburgh, Pittsburgh, PA, USA.,Geisinger Commonwealth School of Medicine, Scranton, PA, USA
| | - Laura P Stabile
- UPMC Hillman Cancer Center, Pittsburgh, PA, USA. .,Department of Pharmacology & Chemical Biology, University of Pittsburgh, Pittsburgh, PA, USA.
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17
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Schmidt S. Promotional Consideration: A Potential Mechanistic Link between Neonicotinoid Insecticides and Hormone-Dependent Breast Cancer. ENVIRONMENTAL HEALTH PERSPECTIVES 2018; 126:114001. [PMID: 30499692 PMCID: PMC6371762 DOI: 10.1289/ehp4097] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/25/2018] [Accepted: 07/03/2018] [Indexed: 05/27/2023]
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18
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Wagner AK, Kumar RG. TBI Rehabilomics Research: Conceptualizing a humoral triad for designing effective rehabilitation interventions. Neuropharmacology 2018; 145:133-144. [PMID: 30222984 DOI: 10.1016/j.neuropharm.2018.09.011] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2018] [Revised: 08/14/2018] [Accepted: 09/10/2018] [Indexed: 12/11/2022]
Abstract
Most areas of medicine use biomarkers in some capacity to aid in understanding how personal biology informs clinical care. This article draws upon the Rehabilomics research model as a translational framework for programs of precision rehabilitation and intervention research focused on linking personal biology to treatment response using biopsychosocial constructs that broadly represent function and that can be applied to many clinical populations with disability. The summary applies the Rehabilomics research framework to the population with traumatic brain injury (TBI) and emphasizes a broad vision for biomarker inclusion, beyond typical brain-derived biomarkers, to capture and/or reflect important neurological and non-neurological pathology associated with TBI as a chronic condition. Humoral signaling molecules are explored as important signaling and regulatory drivers of these chronic conditions and their impact on function. Importantly, secondary injury cascades involved in the humoral triad are influenced by the systemic response to TBI and the development of non-neurological organ dysfunction (NNOD). Biomarkers have been successfully leveraged in other medical fields to inform pre-randomization patient selection for clinical trials, however, this practice largely has not been utilized in TBI research. As such, the applicability of the Rehabilomics research model to contemporary clinical trials and comparative effectiveness research designs for neurological and rehabilitation populations is emphasized. Potential points of intervention to modify inflammation, hormonal, or neurotrophic support through rehabilitation interventions are discussed. This article is part of the Special Issue entitled "Novel Treatments for Traumatic Brain Injury".
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Affiliation(s)
- A K Wagner
- Department of Physical Medicine & Rehabilitation, University of Pittsburgh, USA; Safar Center for Resuscitation Research, University of Pittsburgh, USA; Department of Neuroscience, University of Pittsburgh, USA; Center for Neuroscience, University of Pittsburgh, USA.
| | - R G Kumar
- Department of Physical Medicine & Rehabilitation, University of Pittsburgh, USA; Safar Center for Resuscitation Research, University of Pittsburgh, USA; Department of Epidemiology, University of Pittsburgh, USA
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19
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Rakholia MV, Kumar RG, Oh BM, Ranganathan PR, Berga SL, Kochanek PM, Wagner AK. Systemic Estrone Production and Injury-Induced Sex Hormone Steroidogenesis after Severe Traumatic Brain Injury: A Prognostic Indicator of Traumatic Brain Injury-Related Mortality. J Neurotrauma 2018; 36:1156-1167. [PMID: 29947289 DOI: 10.1089/neu.2018.5782] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022] Open
Abstract
Extensive pre-clinical studies suggest that sex steroids are neuroprotective in experimental traumatic brain injury (TBI). However, clinical trials involving sex hormone administration have not shown beneficial results, and our observational cohort studies show systemic estradiol (E2) production to be associated with adverse outcomes. Systemic E2 is produced via aromatization of testosterone (T) or reduction of estrone (E1). E1, also produced via aromatization of androstenedione (Andro) and is a marker of T-independent E2 production. We hypothesized that E1 would be (1) associated with TBI-related mortality, (2) the primary intermediate for E2 production, and (3) associated with adipose tissue-specific aromatase transcription. We assessed 100 subjects with severe TBI and 8 healthy controls. Serum levels were measured on days 0-3 post-TBI for key steroidogenic precursors (progesterone), aromatase pathway intermediates (E1, E2, T, Andro), and the adipose tissue-specific aromatase transcription factors cortisol, tumor necrosis factor-alpha (TNF-α), and interleukin-6 (IL-6). E1 was elevated after TBI versus controls. High E1 was associated with higher progesterone, cortisol, and IL-6 (p < 0.05). Multivariable logistic regression demonstrated that those in the highest E1 tertile had increased odds for mortality (adjusted OR = 5.656, 95% CI = 1.102-29.045, p = 0.038). Structural equation models show that early serum E2 production is largely T independent, occurring predominantly through E1 metabolism. Acute serum E1 functions as a mortality marker for TBI through aromatase-dependent E1 production and T-independent E2 production. Further work should evaluate risk factors for high E2 production and how systemic E2 and its key intermediate E1 contribute to the extracerebral consequences of severe TBI.
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Affiliation(s)
- Milap V Rakholia
- 1 Department of Physical Medicine and Rehabilitation, University of Pittsburgh, Pittsburgh Pennsylvania
| | - Raj G Kumar
- 1 Department of Physical Medicine and Rehabilitation, University of Pittsburgh, Pittsburgh Pennsylvania
| | - Byung-Mo Oh
- 2 Department of Rehabilitation Medicine, Seoul National University College of Medicine, Seoul National University Hospital, Seoul, South Korea
| | - Prerna R Ranganathan
- 1 Department of Physical Medicine and Rehabilitation, University of Pittsburgh, Pittsburgh Pennsylvania
| | - Sarah L Berga
- 3 Department of Obstetrics and Gynecology, Wake Forest University School of Medicine, Winston-Salem, North Carolina
| | - Patrick M Kochanek
- 4 Department of Critical Care Medicine, University of Pittsburgh, Pittsburgh Pennsylvania.,5 Department of Safar Center for Resuscitation Research, University of Pittsburgh, Pittsburgh Pennsylvania
| | - Amy K Wagner
- 1 Department of Physical Medicine and Rehabilitation, University of Pittsburgh, Pittsburgh Pennsylvania.,5 Department of Safar Center for Resuscitation Research, University of Pittsburgh, Pittsburgh Pennsylvania.,6 Department of Neuroscience, University of Pittsburgh, Pittsburgh Pennsylvania.,7 Department of Center for Neuroscience, University of Pittsburgh, Pittsburgh Pennsylvania
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20
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Golemis EA, Scheet P, Beck TN, Scolnick EM, Hunter DJ, Hawk E, Hopkins N. Molecular mechanisms of the preventable causes of cancer in the United States. Genes Dev 2018; 32:868-902. [PMID: 29945886 PMCID: PMC6075032 DOI: 10.1101/gad.314849.118] [Citation(s) in RCA: 100] [Impact Index Per Article: 14.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Annually, there are 1.6 million new cases of cancer and nearly 600,000 cancer deaths in the United States alone. The public health burden associated with these numbers has motivated enormous research efforts into understanding the root causes of cancer. These efforts have led to the recognition that between 40% and 45% of cancers are associated with preventable risk factors and, importantly, have identified specific molecular mechanisms by which these exposures modify human physiology to induce or promote cancer. The increasingly refined knowledge of these mechanisms, which we summarize here, emphasizes the need for greater efforts toward primary cancer prevention through mitigation of modifiable risk factors. It also suggests exploitable avenues for improved secondary prevention (which includes the development of therapeutics designed for cancer interception and enhanced techniques for noninvasive screening and early detection) based on detailed knowledge of early neoplastic pathobiology. Such efforts would complement the current emphasis on the development of therapeutic approaches to treat established cancers and are likely to result in far greater gains in reducing morbidity and mortality.
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Affiliation(s)
- Erica A Golemis
- Program in Molecular Therapeutics, Fox Chase Cancer Center, Philadelphia, Pennsylvania 19111, USA
| | - Paul Scheet
- Department of Epidemiology, University of Texas M.D. Anderson Cancer Center, Houston, Texas 77030, USA
| | - Tim N Beck
- Program in Molecular Therapeutics, Fox Chase Cancer Center, Philadelphia, Pennsylvania 19111, USA
- Molecular and Cell Biology and Genetics Program, Drexel University College of Medicine, Philadelphia, Pennsylvania 19129, USA
| | - Eward M Scolnick
- Eli and Edythe L. Broad Institute of the Massachusetts Institute of Technology and Harvard University, Cambridge, Massachusetts 02142, USA
| | - David J Hunter
- Nuffield Department of Population Health, University of Oxford, Medical Sciences Division, Oxford OX3 7LF, United Kingdom
| | - Ernest Hawk
- Division of Cancer Prevention and Population Sciences, University of Texas M.D. Anderson Cancer Center, Houston Texas 77030, USA
| | - Nancy Hopkins
- Koch Institute for Integrative Cancer Research, Biology Department, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA
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21
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Makhoul I, Atiq M, Alwbari A, Kieber-Emmons T. Breast Cancer Immunotherapy: An Update. BREAST CANCER-BASIC AND CLINICAL RESEARCH 2018; 12:1178223418774802. [PMID: 29899661 PMCID: PMC5985550 DOI: 10.1177/1178223418774802] [Citation(s) in RCA: 42] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/12/2017] [Accepted: 04/08/2018] [Indexed: 12/22/2022]
Abstract
The immune system plays a major role in cancer surveillance. Harnessing its power to treat many cancers is now a reality that has led to cures in hopeless situations where no other solutions were available from traditional anticancer drugs. These spectacular achievements rekindled the oncology community's interest in extending the benefits to all cancers including breast cancer. The first section of this article reviews the biological foundations of the immune response to different subtypes of breast cancer and the ways cancer may overcome the immune attack leading to cancer disease. The second section is dedicated to the actual immune treatments including breast cancer vaccines, checkpoint inhibitors, monoclonal antibodies, and the "unconventional" immune role of chemotherapy.
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Affiliation(s)
- Issam Makhoul
- Divisions of Hematology and Medical Oncology, Department of Internal Medicine, University of Arkansas for Medical Sciences, Little Rock, AR, USA
| | - Mohammad Atiq
- Department of Internal Medicine, University of Arkansas for Medical Sciences, Little Rock, AR, USA
| | - Ahmed Alwbari
- Divisions of Hematology and Medical Oncology, Department of Internal Medicine, University of Arkansas for Medical Sciences, Little Rock, AR, USA
| | - Thomas Kieber-Emmons
- Department of Pathology, University of Arkansas for Medical Sciences, Little Rock, AR, USA
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22
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Himbert C, Delphan M, Scherer D, Bowers LW, Hursting S, Ulrich CM. Signals from the Adipose Microenvironment and the Obesity-Cancer Link-A Systematic Review. Cancer Prev Res (Phila) 2018; 10:494-506. [PMID: 28864539 DOI: 10.1158/1940-6207.capr-16-0322] [Citation(s) in RCA: 128] [Impact Index Per Article: 18.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2016] [Revised: 06/06/2017] [Accepted: 07/11/2017] [Indexed: 12/13/2022]
Abstract
Obesity and its associated metabolic dysregulation are established risk factors for many cancers. However, the biologic mechanisms underlying this relationship remain incompletely understood. Given the rising rates of both obesity and cancer worldwide, and the challenges for many people to lose excess adipose tissue, a systematic approach to identify potential molecular and metabolic targets is needed to develop effective mechanism-based strategies for the prevention and control of obesity-driven cancer. Epidemiologic, clinical, and preclinical data suggest that within the growth-promoting, proinflammatory microenvironment accompanying obesity, crosstalk between adipose tissue (comprised of adipocytes, macrophages and other cells) and cancer-prone cells may occur via obesity-associated hormones, cytokines, and other mediators that have been linked to increased cancer risk and/or progression. We report here a systematic review on the direct "crosstalk" between adipose tissue and carcinomas in humans. We identified 4,641 articles with n = 20 human clinical studies, which are summarized as: (i) breast (n = 7); (ii) colorectal (n = 4); (iii) esophageal (n = 2); (iv) esophageal/colorectal (n = 1); (v) endometrial (n = 1); (vi) prostate (n = 4); and (vii) ear-nose-throat (ENT) cancer (n = 1). Findings from these clinical studies reinforce preclinical data and suggest organ-dependent crosstalk between adipose tissue and carcinomas via VEGF, IL6, TNFα, and other mechanisms. Moreover, visceral white adipose tissue plays a more central role, as it is more bioenergetically active and is associated with a more procancer secretome than subcutaneous adipose tissue. Efforts to eavesdrop and ultimately interfere with this cancer-enhancing crosstalk may lead to new targets and strategies for decreasing the burden of obesity-related cancers. Cancer Prev Res; 10(9); 494-506. ©2017 AACR.
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Affiliation(s)
- Caroline Himbert
- Huntsman Cancer Institute, Population Sciences, Salt Lake City, Utah.,Department of Population Health Sciences, University of Utah, Salt Lake City, Utah
| | - Mahmoud Delphan
- Huntsman Cancer Institute, Population Sciences, Salt Lake City, Utah.,Department of Population Health Sciences, University of Utah, Salt Lake City, Utah.,Exercise Immunology, Physical Education and Sport Sciences Department, Tarbiat Modares University, Tehran, Iran
| | - Dominique Scherer
- Institute of Medical Biometry and Informatics, University of Heidelberg, Heidelberg, Germany
| | - Laura W Bowers
- Department of Nutrition, University of North Carolina, Chapel Hill, North Carolina
| | - Stephen Hursting
- Department of Nutrition, University of North Carolina, Chapel Hill, North Carolina
| | - Cornelia M Ulrich
- Huntsman Cancer Institute, Population Sciences, Salt Lake City, Utah. .,Department of Population Health Sciences, University of Utah, Salt Lake City, Utah
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23
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Gérard C, Brown KA. Obesity and breast cancer - Role of estrogens and the molecular underpinnings of aromatase regulation in breast adipose tissue. Mol Cell Endocrinol 2018; 466:15-30. [PMID: 28919302 DOI: 10.1016/j.mce.2017.09.014] [Citation(s) in RCA: 79] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/12/2017] [Revised: 09/12/2017] [Accepted: 09/13/2017] [Indexed: 12/15/2022]
Abstract
One in eight women will develop breast cancer over their lifetime making it the most common female cancer. The cause of breast cancer is multifactorial and includes hormonal, genetic and environmental cues. Obesity is now an accepted risk factor for breast cancer in postmenopausal women, particularly for the hormone-dependent subtype of breast cancer. Obesity, which is characterized by an excess accumulation of body fat, is at the origin of chronic inflammation of white adipose tissue and is associated with dramatic changes in the biology of adipocytes leading to their dysfunction. Inflammatory factors found in the breast of obese women considerably impact estrogen signaling, mainly by driving changes in aromatase expression the enzyme responsible for estrogen production, and therefore promote tumor formation and progression. There is thus a strong link between adipose inflammation and estrogen biosynthesis and their signaling pathways converge in obese patients. This review describes how obesity-related factors can affect the risk of hormone-dependent breast cancer, highlighting the different molecular mechanisms and metabolic pathways involved in aromatase regulation, estrogen production and breast malignancy in the context of obesity.
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Affiliation(s)
- Céline Gérard
- Metabolism & Cancer Laboratory, Hudson Institute of Medical Research, Clayton, VIC, Australia
| | - Kristy A Brown
- Metabolism & Cancer Laboratory, Hudson Institute of Medical Research, Clayton, VIC, Australia; Department of Physiology, Monash University, Clayton, VIC, Australia; Department of Medicine, Weill Cornell Medicine, New York, NY, USA.
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24
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Caron-Beaudoin É, Viau R, Sanderson JT. Effects of Neonicotinoid Pesticides on Promoter-Specific Aromatase (CYP19) Expression in Hs578t Breast Cancer Cells and the Role of the VEGF Pathway. ENVIRONMENTAL HEALTH PERSPECTIVES 2018; 126:047014. [PMID: 29701941 PMCID: PMC6071809 DOI: 10.1289/ehp2698] [Citation(s) in RCA: 66] [Impact Index Per Article: 9.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/17/2017] [Revised: 03/23/2018] [Accepted: 03/26/2018] [Indexed: 05/06/2023]
Abstract
BACKGROUND Aromatase (CYP19) is a key enzyme in estrogens biosynthesis. In the mammary gland, CYP19 gene is expressed at low levels under the regulation of its I.4 promoter. In hormone-dependent breast cancer, fibroblast cells surrounding the tumor express increased levels of CYP19 mRNA due to a decrease of I.4 promoter activity and an increase of PII, I.3, and I.7 promoter activity. Little is known about the effects of environmental chemicals on the promoter-specific CYP19 expression. OBJECTIVE We aimed to determine the effects of two neonicotinoids (thiacloprid and imidacloprid) on promoter-specific CYP19 expression in Hs578t breast cancer cells and understand the signaling pathways involved. METHODS Hs578t cells were exposed to various signaling pathway stimulants or neonicotinoids for 24 h. Promoter-specific expression of CYP19 was determined by real-time quantitative polymerase chain reaction and catalytic activity of aromatase by tritiated water release assay. RESULTS To our knowledge, we are the first to demonstrate that the normal I.4 promoter and the breast cancer-relevant PII, I.3, and I.7 promoters of CYP19 are active in these cells. We found that the expression of CYP19 via promoters PII, I.3, and I.7 in Hs578t cells was, in part, dependent on the activation of two VEGF signaling pathways: mitogen-activated protein kinase (MAPK) 1/3 and phospholipase C (PLC). Exposure of Hs578t cells to environmental concentrations of imidacloprid and thiacloprid resulted in a switch in CYP19 promoter usage, involving inhibition of I.4 promoter activity and an increase of PII, I.3, and I.7 promoter-mediated CYP19 expression and aromatase catalytic activity. Greater effects were seen at lower concentrations. Our results suggest that thiacloprid and imidacloprid exert their effects at least partially by inducing the MAPK 1/3 and/or PLC pathways. CONCLUSIONS We demonstrated in vitro that neonicotinoids may stimulate a change in CYP19 promoter usage similar to that observed in patients with hormone-dependent breast cancer. https://doi.org/10.1289/EHP2698.
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Affiliation(s)
- Élyse Caron-Beaudoin
- INRS – Institut Armand-Frappier, Université du Québec, Laval, Quebec, Canada
- Department of Occupational and Environmental Health, School of Public Health, Université de Montréal, Montreal, Quebec, Canada
| | - Rachel Viau
- INRS – Institut Armand-Frappier, Université du Québec, Laval, Quebec, Canada
| | - J Thomas Sanderson
- INRS – Institut Armand-Frappier, Université du Québec, Laval, Quebec, Canada
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26
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Pedersen AL, Brownrout JL, Saldanha CJ. Neuroinflammation and neurosteroidogenesis: Reciprocal modulation during injury to the adult zebra finch brain. Physiol Behav 2018; 187:51-56. [DOI: 10.1016/j.physbeh.2017.10.013] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2017] [Revised: 10/11/2017] [Accepted: 10/11/2017] [Indexed: 01/10/2023]
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The Role of the Estrogen Pathway in the Tumor Microenvironment. Int J Mol Sci 2018; 19:ijms19020611. [PMID: 29463044 PMCID: PMC5855833 DOI: 10.3390/ijms19020611] [Citation(s) in RCA: 136] [Impact Index Per Article: 19.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2018] [Revised: 02/13/2018] [Accepted: 02/16/2018] [Indexed: 12/15/2022] Open
Abstract
Estrogen receptors are broadly expressed in many cell types involved in the innate and adaptive immune responses, and differentially regulate the production of cytokines. While both genomic and non-genomic tumor cell promoting mechanisms of estrogen signaling are well characterized in multiple carcinomas including breast, ovarian, and lung, recent investigations have identified a potential immune regulatory role of estrogens in the tumor microenvironment. Tumor immune tolerance is a well-established mediator of oncogenesis, with increasing evidence indicating the importance of the immune response in tumor progression. Immune-based therapies such as antibodies that block checkpoint signals have emerged as exciting therapeutic approaches for cancer treatment, offering durable remissions and prolonged survival. However, only a subset of patients demonstrate clinical response to these agents, prompting efforts to elucidate additional immunosuppressive mechanisms within the tumor microenvironment. Evidence drawn from multiple cancer types, including carcinomas traditionally classified as non-immunogenic, implicate estrogen as a potential mediator of immunosuppression through modulation of protumor responses independent of direct activity on tumor cells. Herein, we review the interplay between estrogen and the tumor microenvironment and the clinical implications of endocrine therapy as a novel treatment strategy within immuno-oncology.
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Goldberg R, Sonnenblick A, Hermano E, Hamburger T, Meirovitz A, Peretz T, Elkin M. Heparanase augments insulin receptor signaling in breast carcinoma. Oncotarget 2017; 8:19403-19412. [PMID: 28038446 PMCID: PMC5386693 DOI: 10.18632/oncotarget.14292] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2016] [Accepted: 12/01/2016] [Indexed: 01/09/2023] Open
Abstract
Recently, growing interest in the potential link between metabolic disorders (i.e., diabetes, obesity, metabolic syndrome) and breast cancer has mounted, including studies which indicate that diabetic/hyperinsulinemic women have a significantly higher risk of bearing breast tumors that are more aggressive and associated with higher death rates. Insulin signaling is regarded as a major contributor to this phenomenon; much less is known about the role of heparan sulfate-degrading enzyme heparanase in the link between metabolic disorders and cancer.In the present study we analyzed clinical samples of breast carcinoma derived from diabetic/non-diabetic patients, and investigated effects of heparanase on insulin signaling in breast carcinoma cell lines, as well as insulin-driven growth of breast tumor cells.We demonstrate that heparanase activity leads to enhanced insulin signaling and activation of downstream tumor-promoting pathways in breast carcinoma cells. In agreement, heparanase enhances insulin-induced proliferation of breast tumor cells in vitro. Moreover, analyzing clinical data from diabetic breast carcinoma patients, we found that concurrent presence of both diabetic state and heparanase in tumor tissue (as opposed to either condition alone) was associated with more aggressive phenotype of breast tumors in the patient cohort analyzed in our study (two-sided Fisher's exact test; p=0.04). Our findings highlight the emerging role of heparanase in powering effect of hyperinsulinemic state on breast tumorigenesis and imply that heparanase targeting, which is now under intensive development/clinical testing, could be particularly efficient in a growing fraction of breast carcinoma patients suffering from metabolic disorders.
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Affiliation(s)
- Rachel Goldberg
- Sharett Institute, Hadassah-Hebrew University Medical Center, Jerusalem 91120, Israel
| | - Amir Sonnenblick
- Sharett Institute, Hadassah-Hebrew University Medical Center, Jerusalem 91120, Israel
| | - Esther Hermano
- Sharett Institute, Hadassah-Hebrew University Medical Center, Jerusalem 91120, Israel
| | - Tamar Hamburger
- Sharett Institute, Hadassah-Hebrew University Medical Center, Jerusalem 91120, Israel
| | - Amichay Meirovitz
- Sharett Institute, Hadassah-Hebrew University Medical Center, Jerusalem 91120, Israel
| | - Tamar Peretz
- Sharett Institute, Hadassah-Hebrew University Medical Center, Jerusalem 91120, Israel
| | - Michael Elkin
- Sharett Institute, Hadassah-Hebrew University Medical Center, Jerusalem 91120, Israel
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Shao X, Luo L, Guo Y, Xu X, Deng D, Feng J, Ding Y, Mou H, Huang P, Shi L, Huang Y, Ye W, Lou C, Chen Z, Zheng Y, Wang X. Rs1008805 polymorphism of CYP19A1 gene is associated with the efficacy of hormone therapy in stage I-II and operable stage III breast cancer. Oncol Lett 2017; 14:6156-6162. [PMID: 29113261 DOI: 10.3892/ol.2017.6984] [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: 01/01/2016] [Accepted: 05/23/2017] [Indexed: 11/06/2022] Open
Abstract
It has been hypothesized that single nucleotide polymorphisms in CYP19A1 gene may alter aromatase activity and circulating steroid hormone levels in females. Therefore, it is biologically reasonable that CYP19A1 rs1008805 (A/G) polymorphism may be associated with the clinical outcome of hormone therapy. Genotyping for the CYP19A1 rs1008805 polymorphism was performed for 287 females with hormone receptor (HR)-positive early breast cancer, and potential associations were evaluated between CYP19A1 rs1008805 genotypes and disease-free survival (DFS). Based on the analysis of the whole cohort, no significant differences were observed between rs1008805 genotypes and DFS. However, in postmenopausal females, rs1008805 variants were significantly associated with DFS (AA vs. AG vs. GG, 89.2 vs. 58.2 vs. 32.7 months; P=0.019). In addition, when the population was divided into two cohorts, females with the GG variant exhibited a significantly poorer DFS [GG vs. AA or AG, 32.7 vs. 70.6 months; hazard ratio (HR), 3.613; 95% confidence interval (CI), 1.380-9.457; P=0.005]. Furthermore, when adjusted for other patient features in multivariate analyses, GG genotype remained an independent prognostic marker for DFS (HR, 3.439; 95% CI, 1.251-9.456; P=0.017). However, there were no significant differences in DFS between patients harboring the minor allele and those with the homozygous common allele (AG or GG vs. AA, 52.4 vs. 89.2 months; HR, 1.288; 95% CI, 0.705-2.353; P=0.408). There were also no associations between rs1008805 polymorphism and DFS for premenopausal females. In conclusion, the homozygous minor allele (GG) of CYP19A1 rs1008805 was identified to be significantly associated with an inferior clinical outcome of hormone therapy in postmenopausal hormone receptor-positive patients with early breast cancer. If confirmed by further study, genotyping for CYP19A1 rs1008805 polymorphism may provide predictive information to improve the selection of endocrine treatment.
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Affiliation(s)
- Xiying Shao
- Department of Medical Oncology, Zhejiang Cancer Hospital, Hangzhou, Zhejiang 310022, P.R. China
| | - Lei Luo
- Zhejiang Institute for Food and Drug Control, Hangzhou, Zhejiang 310052, P.R. China
| | - Yong Guo
- Department of Medical Oncology, The First Affiliated Hospital of Zhejiang Traditional Chinese Medical University, Hangzhou, Zhejiang 310006, P.R. China
| | - Xiaohong Xu
- Clinical Laboratory, Zhejiang Cancer Hospital, Hangzhou, Zhejiang 310022, P.R. China
| | - Dehou Deng
- Department of Medical Oncology, Zhejiang Cancer Hospital, Hangzhou, Zhejiang 310022, P.R. China
| | - Jianguo Feng
- Cancer Research Institute, Zhejiang Cancer Hospital, Hangzhou, Zhejiang 310022, P.R. China
| | - Yuheng Ding
- Department of Medical Oncology, The First Affiliated Hospital of Zhejiang Traditional Chinese Medical University, Hangzhou, Zhejiang 310006, P.R. China
| | - Hanzhou Mou
- Cancer Research Institute, Zhejiang Cancer Hospital, Hangzhou, Zhejiang 310022, P.R. China
| | - Ping Huang
- Department of Medical Oncology, Zhejiang Cancer Hospital, Hangzhou, Zhejiang 310022, P.R. China
| | - Lei Shi
- Department of Medical Oncology, Zhejiang Cancer Hospital, Hangzhou, Zhejiang 310022, P.R. China
| | - Yuan Huang
- Department of Medical Oncology, Zhejiang Cancer Hospital, Hangzhou, Zhejiang 310022, P.R. China
| | - Weiwu Ye
- Department of Medical Oncology, Zhejiang Cancer Hospital, Hangzhou, Zhejiang 310022, P.R. China
| | - Caijin Lou
- Department of Medical Oncology, Zhejiang Cancer Hospital, Hangzhou, Zhejiang 310022, P.R. China
| | - Zhanhong Chen
- Department of Medical Oncology, Zhejiang Cancer Hospital, Hangzhou, Zhejiang 310022, P.R. China
| | - Yabing Zheng
- Department of Medical Oncology, Zhejiang Cancer Hospital, Hangzhou, Zhejiang 310022, P.R. China
| | - Xiaojia Wang
- Department of Medical Oncology, Zhejiang Cancer Hospital, Hangzhou, Zhejiang 310022, P.R. China
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Serrano-Gómez SJ, Sanabria-Salas MC, Garay J, Baddoo MC, Hernández-Suarez G, Mejía JC, García O, Miele L, Fejerman L, Zabaleta J. Ancestry as a potential modifier of gene expression in breast tumors from Colombian women. PLoS One 2017; 12:e0183179. [PMID: 28832682 PMCID: PMC5568388 DOI: 10.1371/journal.pone.0183179] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2017] [Accepted: 07/31/2017] [Indexed: 01/24/2023] Open
Abstract
Background Hispanic/Latino populations are a genetically admixed and heterogeneous group, with variable fractions of European, Indigenous American and African ancestries. The molecular profile of breast cancer has been widely described in non-Hispanic Whites but equivalent knowledge is lacking in Hispanic/Latinas. We have previously reported that the most prevalent breast cancer intrinsic subtype in Colombian women was Luminal B as defined by St. Gallen 2013 criteria. In this study we explored ancestry-associated differences in molecular profiles of Luminal B tumors among these highly admixed women. Methods We performed whole-transcriptome RNA-seq analysis in 42 Luminal tumors (21 Luminal A and 21 Luminal B) from Colombian women. Genetic ancestry was estimated from a panel of 80 ancestry-informative markers (AIM). We categorized patients according to Luminal subtype and to the proportion of European and Indigenous American ancestry and performed differential expression analysis comparing Luminal B against Luminal A tumors according to the assigned ancestry groups. Results We found 5 genes potentially modulated by genetic ancestry: ERBB2 (log2FC = 2.367, padj<0.01), GRB7 (log2FC = 2.327, padj<0.01), GSDMB (log2FC = 1.723, padj<0.01, MIEN1 (log2FC = 2.195, padj<0.01 and ONECUT2 (log2FC = 2.204, padj<0.01). In the replication set we found a statistical significant association between ERBB2 expression with Indigenous American ancestry (p = 0.02, B = 3.11). This association was not biased by the distribution of HER2+ tumors among the groups analyzed. Conclusions Our results suggest that genetic ancestry in Hispanic/Latina women might modify ERBB2 gene expression in Luminal tumors. Further analyses are needed to confirm these findings and explore their prognostic value.
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Affiliation(s)
- Silvia J. Serrano-Gómez
- Grupo de investigación en Biología del Cáncer, Instituto Nacional de Cancerología, Bogotá D. C, Colombia
- Programa de doctorado en Ciencias Biológicas, Pontificia Universidad Javeriana, Bogotá D. C, Colombia
| | | | - Jone Garay
- Stanley S. Scott Cancer Center, LSUHSC, New Orleans, LA, United States of America
| | - Melody C. Baddoo
- Tulane University School of Medicine, New Orleans, LA, United States of America
| | - Gustavo Hernández-Suarez
- Grupo de investigación en Biología del Cáncer, Instituto Nacional de Cancerología, Bogotá D. C, Colombia
| | - Juan Carlos Mejía
- Grupo de Patología, Instituto Nacional de Cancerología, Bogotá D. C, Colombia
| | - Oscar García
- Grupo de Seno y Tejidos blandos, Instituto Nacional de Cancerología, Bogotá D. C, Colombia
| | - Lucio Miele
- Department of Genetics, LSUHSC, New Orleans, LA, United States of America
| | - Laura Fejerman
- Department of Medicine, Institute of Human Genetics, University of California San Francisco, San Francisco, CA, United States of America
| | - Jovanny Zabaleta
- Stanley S. Scott Cancer Center, LSUHSC, New Orleans, LA, United States of America
- Department of Pediatrics, LSUHSC, New Orleans, United States of America
- * E-mail:
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Crespi E, Bottai G, Santarpia L. Role of inflammation in obesity-related breast cancer. Curr Opin Pharmacol 2016; 31:114-122. [PMID: 27889687 DOI: 10.1016/j.coph.2016.11.004] [Citation(s) in RCA: 43] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2016] [Revised: 10/25/2016] [Accepted: 11/07/2016] [Indexed: 02/04/2023]
Abstract
Chronic inflammation associated with obesity is now recognized to be an important condition in promoting carcinogenesis and progression in breast cancer patients, mostly in postmenopausal women with tumors expressing estrogen and progesterone receptors. In obese patients, altered levels of several inflammatory mediators regulating aromatase and estrogen expression are one of the mechanisms responsible of increase breast cancer risk. Growing attention has also been paid to the local adipose inflammation and the role played by macrophages as determinants of breast cancer risk recurrence and prognosis. The inflammation-obesity axis offers different molecular signaling pathways for therapeutic interventions and potential pharmacological targets. The increasing rate of obesity worldwide associated with the recent findings linking inflammation and breast cancer urge further investigation.
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Affiliation(s)
- Elisa Crespi
- Oncology Experimental Therapeutics, IRCCS Humanitas Clinical and Research Center, Rozzano, Milan, Italy
| | - Giulia Bottai
- Oncology Experimental Therapeutics, IRCCS Humanitas Clinical and Research Center, Rozzano, Milan, Italy
| | - Libero Santarpia
- Oncology Experimental Therapeutics, IRCCS Humanitas Clinical and Research Center, Rozzano, Milan, Italy.
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Iyengar NM, Gucalp A, Dannenberg AJ, Hudis CA. Obesity and Cancer Mechanisms: Tumor Microenvironment and Inflammation. J Clin Oncol 2016; 34:4270-4276. [PMID: 27903155 DOI: 10.1200/jco.2016.67.4283] [Citation(s) in RCA: 644] [Impact Index Per Article: 71.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
Purpose There is growing evidence that inflammation is a central and reversible mechanism through which obesity promotes cancer risk and progression. Methods We review recent findings regarding obesity-associated alterations in the microenvironment and the local and systemic mechanisms through which these changes support tumor growth. Results Locally, hyperadiposity is associated with altered adipose tissue function, adipocyte death, and chronic low-grade inflammation. Most individuals who are obese harbor inflamed adipose tissue, which resembles chronically injured tissue, with immune cell infiltration and remodeling. Within this distinctly altered local environment, several pathophysiologic changes are found that may promote breast and other cancers. Consistently, adipose tissue inflammation is associated with a worse prognosis in patients with breast and tongue cancers. Systemically, the metabolic syndrome, including dyslipidemia and insulin resistance, occurs in the setting of adipose inflammation and operates in concert with local mechanisms to sustain the inflamed microenvironment and promote tumor growth. Importantly, adipose inflammation and its protumor consequences can be found in some individuals who are not considered to be obese or overweight by body mass index. Conclusion The tumor-promoting effects of obesity occur at the local level via adipose inflammation and associated alterations in the microenvironment, as well as systemically via circulating metabolic and inflammatory mediators associated with adipose inflammation. Accurately characterizing the obese state and identifying patients at increased risk for cancer development and progression will likely require more precise assessments than body mass index alone. Biomarkers of adipose tissue inflammation would help to identify high-risk populations. Moreover, adipose inflammation is a reversible process and represents a novel therapeutic target that warrants further study to break the obesity-cancer link.
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Affiliation(s)
- Neil M Iyengar
- Neil M. Iyengar, Ayca Gucalp, and Clifford A. Hudis, Memorial Sloan Kettering Cancer Center; Neil M. Iyengar, Ayca Gucalp, Andrew J. Dannenberg, and Clifford A. Hudis, Weill Cornell Medical College, New York, NY
| | - Ayca Gucalp
- Neil M. Iyengar, Ayca Gucalp, and Clifford A. Hudis, Memorial Sloan Kettering Cancer Center; Neil M. Iyengar, Ayca Gucalp, Andrew J. Dannenberg, and Clifford A. Hudis, Weill Cornell Medical College, New York, NY
| | - Andrew J Dannenberg
- Neil M. Iyengar, Ayca Gucalp, and Clifford A. Hudis, Memorial Sloan Kettering Cancer Center; Neil M. Iyengar, Ayca Gucalp, Andrew J. Dannenberg, and Clifford A. Hudis, Weill Cornell Medical College, New York, NY
| | - Clifford A Hudis
- Neil M. Iyengar, Ayca Gucalp, and Clifford A. Hudis, Memorial Sloan Kettering Cancer Center; Neil M. Iyengar, Ayca Gucalp, Andrew J. Dannenberg, and Clifford A. Hudis, Weill Cornell Medical College, New York, NY
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Abdelmagid SA, MacKinnon JL, Janssen SM, Ma DWL. Role of n-3 Polyunsaturated Fatty Acids and Exercise in Breast Cancer Prevention: Identifying Common Targets. Nutr Metab Insights 2016; 9:71-84. [PMID: 27812288 PMCID: PMC5089819 DOI: 10.4137/nmi.s39043] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2016] [Revised: 08/18/2016] [Accepted: 08/23/2016] [Indexed: 12/21/2022] Open
Abstract
Diet and exercise are recognized as important lifestyle factors that significantly influence breast cancer risk. In particular, dietary n-3 polyunsaturated fatty acids (PUFAs) have been shown to play an important role in breast cancer prevention. Growing evidence also demonstrates a role for exercise in cancer and chronic disease prevention. However, the potential synergistic effect of n-3 PUFA intake and exercise is yet to be determined. This review explores targets for breast cancer prevention that are common between n-3 PUFA intake and exercise and that may be important study outcomes for future research investigating the combined effect of n-3 PUFA intake and exercise. These lines of evidence highlight potential new avenues for research and strategies for breast cancer prevention.
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Affiliation(s)
- Salma A Abdelmagid
- Department of Human Health and Nutritional Sciences, College of Biological Science, University of Guelph, Guelph, Ontario, Canada
| | - Jessica L MacKinnon
- Department of Human Health and Nutritional Sciences, College of Biological Science, University of Guelph, Guelph, Ontario, Canada
| | - Sarah M Janssen
- Department of Human Health and Nutritional Sciences, College of Biological Science, University of Guelph, Guelph, Ontario, Canada
| | - David W L Ma
- Department of Human Health and Nutritional Sciences, College of Biological Science, University of Guelph, Guelph, Ontario, Canada
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Chan HJ, Petrossian K, Chen S. Structural and functional characterization of aromatase, estrogen receptor, and their genes in endocrine-responsive and -resistant breast cancer cells. J Steroid Biochem Mol Biol 2016; 161:73-83. [PMID: 26277097 PMCID: PMC4752924 DOI: 10.1016/j.jsbmb.2015.07.018] [Citation(s) in RCA: 70] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/23/2015] [Revised: 07/22/2015] [Accepted: 07/29/2015] [Indexed: 11/22/2022]
Abstract
Aromatase and estrogen receptor α (ER) are two key proteins for the proliferation of endocrine-responsive and -resistant breast cancers. Aromatase is an enzyme involved in the conversion of androgen (such as testosterone) to estrogen (such as 17β-estradiol). It is also a very effective therapeutic target for the treatment of endocrine-responsive breast cancer. Comparing endocrine-responsive and -resistant breast cancer, aromatase protein levels do not change significantly. Aromatase activity; however, can be increased via PI3K/Akt/IGFR signaling pathways in endocrine resistant cells. The activity of aromatase has been reported to be modulated by phosphorylation. The ER is an important steroid nuclear receptor in the proliferation of both endocrine-responsive and -resistant cells. Although the mutation or amplification of ER can cause endocrine resistance, it is not commonly found. Some point mutations and translocation events have been characterized and shown to promote estrogen-independent growth. Phosphorylation by cross-talk with growth factor pathways is one of the main mechanisms for ligand-independent activation of ER. Taken together, both ER and aromatase are important in ER-dependent breast cancer and the development of endocrine resistance.
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Affiliation(s)
- Hei Jason Chan
- Department of Cancer Biology, Beckman Research Institute of the City of Hope, Duarte, CA, United States
| | - Karineh Petrossian
- Department of Cancer Biology, Beckman Research Institute of the City of Hope, Duarte, CA, United States
| | - Shiuan Chen
- Department of Cancer Biology, Beckman Research Institute of the City of Hope, Duarte, CA, United States.
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Shin JI, Lim HY, Kim HW, Seung BJ, Ju JH, Sur JH. Analysis of Obesity-Related Factors and their Association with Aromatase Expression in Canine Malignant Mammary Tumours. J Comp Pathol 2016; 155:15-23. [PMID: 27290646 DOI: 10.1016/j.jcpa.2016.05.005] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2016] [Revised: 04/06/2016] [Accepted: 05/07/2016] [Indexed: 12/01/2022]
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Okamoto M, Mizukami Y. GPER negatively regulates TNFα-induced IL-6 production in human breast cancer cells via NF-κB pathway. Endocr J 2016; 63:485-93. [PMID: 26888479 DOI: 10.1507/endocrj.ej15-0571] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/24/2022] Open
Abstract
Estrogen is known to have anti-inflammatory effects, that are thought to be mediated by the classical estrogen receptors (ERs), ERα and ERβ. G protein coupled estrogen receptor1 (GPER) is a novel membrane-type estrogen receptor that can mediate non-genomic estrogenic responses. Although there have been several reports asserting that the participation of GPER in anti-inflammatory effects is induced by estrogen, the role of GPER remains poorly understood. In this study, we investigated the involvement of GPER in the regulation of a representative inflammatory cytokine, IL-6. We first examined the expression of IL-6 mRNA by TNFα stimulation in the transfection of GPER-expression plasmid into HeLa cells. Exogenous GPER significantly inhibited TNFα-induced IL-6 expression, and blocked NF-κB promoter activity inducing the expression of IL-6 in a dose-dependent manner. The promoter activity was restored almost to control level by transfection with the C-terminal deletion mutant of GPER. Similar results have been observed in endogenous GPER using SKBR3 cells which do not express the classical ERs. The data have been validated by treatment of GPER with siRNA. These findings indicate that GPER negatively regulates TNFα-induced IL-6 expression, probably through inhibition of NF-κB promoter activity by a signal(s) derived from the C-terminal region of GPER.
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Affiliation(s)
- Mariko Okamoto
- Laboratory of Veterinary Immunology, School of Veterinary Medicine, Azabu University, Sagamihara 252-5201, Japan
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Dieci MV, Griguolo G, Miglietta F, Guarneri V. The immune system and hormone-receptor positive breast cancer: Is it really a dead end? Cancer Treat Rev 2016; 46:9-19. [PMID: 27055087 DOI: 10.1016/j.ctrv.2016.03.011] [Citation(s) in RCA: 79] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2016] [Accepted: 03/21/2016] [Indexed: 01/08/2023]
Abstract
Even if breast cancer has not been traditionally considered an immunogenic tumor, recent data suggest that immunity, and its interaction with tumor cells and tumor microenvironment, might play an important role in this malignancy, in particular in triple negative and HER2+ subtypes. As no consistent data on the potential clinical relevance of tumor infiltrating lymphocytes have been produced in hormone receptor positive (HR+) HER2- breast cancer, the interest in studying immune aspects in this subtype has become less appealing. Nevertheless, some scattered evidence indicates that immunity and inflammation may be implicated in the biology of this subtype as well. In HR+ breast cancer, the interaction between tumor cells and the immune milieu might rely on different mechanisms than in other BC subtypes, involving the modulation of the tumor microenvironment by mutual interplays of endocrine factors, pro-inflammatory status and immune cells. These subtle mechanisms may require more refined methods of evaluation, such as the assessment of tumor infiltrating lymphocytes subpopulations or gene signatures. In this paper we aim to perform a comprehensive review of pre-clinical and clinical data on the interplay between the immune system and breast cancer in the HR+ subtype, to guide further research in the field.
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Affiliation(s)
- Maria Vittoria Dieci
- Dept. of Surgery, Oncology and Gastroenterology, University of Padova, Padova, Italy; Division of Medical Oncology 2, Istituto Oncologico Veneto IRCCS, Padova, Italy.
| | - Gaia Griguolo
- Dept. of Surgery, Oncology and Gastroenterology, University of Padova, Padova, Italy; Division of Medical Oncology 2, Istituto Oncologico Veneto IRCCS, Padova, Italy
| | - Federica Miglietta
- Division of Medical Oncology 2, Istituto Oncologico Veneto IRCCS, Padova, Italy
| | - Valentina Guarneri
- Dept. of Surgery, Oncology and Gastroenterology, University of Padova, Padova, Italy; Division of Medical Oncology 2, Istituto Oncologico Veneto IRCCS, Padova, Italy
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Williams CB, Yeh ES, Soloff AC. Tumor-associated macrophages: unwitting accomplices in breast cancer malignancy. NPJ Breast Cancer 2016; 2:15025. [PMID: 26998515 PMCID: PMC4794275 DOI: 10.1038/npjbcancer.2015.25] [Citation(s) in RCA: 348] [Impact Index Per Article: 38.7] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2015] [Revised: 12/12/2015] [Accepted: 12/15/2015] [Indexed: 01/01/2023] Open
Abstract
Deleterious inflammation is a primary feature of breast cancer. Accumulating evidence demonstrates that macrophages, the most abundant leukocyte population in mammary tumors, have a critical role at each stage of cancer progression. Such tumor-associated macrophages facilitate neoplastic transformation, tumor immune evasion and the subsequent metastatic cascade. Herein, we discuss the dynamic process whereby molecular and cellular features of the tumor microenvironment act to license tissue-repair mechanisms of macrophages, fostering angiogenesis, metastasis and the support of cancer stem cells. We illustrate how tumors induce, then exploit trophic macrophages to subvert innate and adaptive immune responses capable of destroying malignant cells. Finally, we discuss compelling evidence from murine models of cancer and early clinical trials in support of macrophage-targeted intervention strategies with the potential to dramatically reduce breast cancer morbidity and mortality.
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Affiliation(s)
- Carly Bess Williams
- Department of Cell and Molecular Pharmacology and Experimental Therapeutics, Medical University of South Carolina, Charleston, SC, USA
- Hollings Cancer Center, Medical University of South Carolina, Charleston, SC, USA
| | - Elizabeth S Yeh
- Department of Cell and Molecular Pharmacology and Experimental Therapeutics, Medical University of South Carolina, Charleston, SC, USA
- Hollings Cancer Center, Medical University of South Carolina, Charleston, SC, USA
| | - Adam C Soloff
- Hollings Cancer Center, Medical University of South Carolina, Charleston, SC, USA
- Department of Microbiology and Immunology, Medical University of South Carolina, Charleston, SC, USA
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Argolo DF, Iyengar NM, Hudis CA. Obesity and Cancer: Concepts and Challenges. Indian J Surg Oncol 2015; 6:390-8. [PMID: 27081257 DOI: 10.1007/s13193-015-0483-z] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2015] [Accepted: 11/17/2015] [Indexed: 12/17/2022] Open
Abstract
The rates of overweight and obesity are increasing worldwide in both developed and developing countries. Obesity is a major public health problem as it is associated with many diseases, including diabetes, hypertension, dyslipidemia, atherosclerosis, and some types of cancer. Breast cancer is a malignancy in which both the risk of development and the prognosis are negatively impacted by the obese state. The precise mechanisms pathophysiologically linking obesity and cancer are still under investigation. The biological basis for these associations includes both systemic and local tissue effects and white adipose tissue inflammation appears to be a critical component. A comprehensive understanding of the mechanisms linking obesity, inflammation and cancer may provide an opportunity for the development of strategies to attenuate the negative impact of obesity.
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Affiliation(s)
- Daniel F Argolo
- Memorial Sloan Kettering Cancer Center, 300 East 66th Street - 8th floor, New York, NY 10065 USA ; CLION - CAM Group, Salvador, BA Brazil
| | - Neil M Iyengar
- Memorial Sloan Kettering Cancer Center, 300 East 66th Street - 8th floor, New York, NY 10065 USA ; Weill Cornell Medical College, New York, NY USA
| | - Clifford A Hudis
- Memorial Sloan Kettering Cancer Center, 300 East 66th Street - 8th floor, New York, NY 10065 USA ; Weill Cornell Medical College, New York, NY USA
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40
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Iyengar NM, Hudis CA, Dannenberg AJ. Obesity and inflammation: new insights into breast cancer development and progression. Am Soc Clin Oncol Educ Book 2015:46-51. [PMID: 23714453 DOI: 10.14694/edbook_am.2013.33.46] [Citation(s) in RCA: 85] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
The importance of inflammation in promoting carcinogenesis and tumor progression is well recognized. Chronic inflammation caused by a variety of infectious agents can lead to the development of several common malignancies. Similarly, inflammatory bowel disease is a well-known risk factor for colorectal cancer. Much less is known about the link between inflammation and the development of breast cancer. Recent data suggest that obesity causes both in-breast and systemic inflammation that contribute to the development and progression of breast cancer. This observation has potentially important implications in terms of prevention and treatment of breast cancer, especially given the rising worldwide overweight and obesity rates. Inflamed white adipose tissue (WAT) within the breast is associated with elevated levels of proinflammatory mediators, enhanced expression of aromatase (the rate-limiting enzyme for estrogen biosynthesis), and increased estrogen receptor-α (ER-α)-dependent gene expression. Systemic consequences of obesity including altered adipokine levels, elevated circulating estrogen levels, and insulin resistance are also believed to play a role in the pathogenesis of breast cancer. Collectively, these findings suggest a significant role for inflammation in the pathogenesis of breast cancer in obese and overweight patients.
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Affiliation(s)
- Neil M Iyengar
- From the Memorial Sloan-Kettering Cancer Center, New York, NY; Weill Cornell Medical College, New York, NY
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41
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Iyengar NM, Hudis CA, Dannenberg AJ. Obesity and inflammation: new insights into breast cancer development and progression. AMERICAN SOCIETY OF CLINICAL ONCOLOGY EDUCATIONAL BOOK. AMERICAN SOCIETY OF CLINICAL ONCOLOGY. ANNUAL MEETING 2015. [PMID: 23714453 DOI: 10.1200/edbook_am.2013.33.46] [Citation(s) in RCA: 71] [Impact Index Per Article: 7.1] [Reference Citation Analysis] [Abstract] [Subscribe] [Scholar Register] [Indexed: 01/22/2023]
Abstract
The importance of inflammation in promoting carcinogenesis and tumor progression is well recognized. Chronic inflammation caused by a variety of infectious agents can lead to the development of several common malignancies. Similarly, inflammatory bowel disease is a well-known risk factor for colorectal cancer. Much less is known about the link between inflammation and the development of breast cancer. Recent data suggest that obesity causes both in-breast and systemic inflammation that contribute to the development and progression of breast cancer. This observation has potentially important implications in terms of prevention and treatment of breast cancer, especially given the rising worldwide overweight and obesity rates. Inflamed white adipose tissue (WAT) within the breast is associated with elevated levels of proinflammatory mediators, enhanced expression of aromatase (the rate-limiting enzyme for estrogen biosynthesis), and increased estrogen receptor-α (ER-α)-dependent gene expression. Systemic consequences of obesity including altered adipokine levels, elevated circulating estrogen levels, and insulin resistance are also believed to play a role in the pathogenesis of breast cancer. Collectively, these findings suggest a significant role for inflammation in the pathogenesis of breast cancer in obese and overweight patients.
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Affiliation(s)
- Neil M Iyengar
- From the Memorial Sloan-Kettering Cancer Center, New York, NY; Weill Cornell Medical College, New York, NY
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42
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Integrated Bioinformatics, Environmental Epidemiologic and Genomic Approaches to Identify Environmental and Molecular Links between Endometriosis and Breast Cancer. Int J Mol Sci 2015; 16:25285-322. [PMID: 26512648 PMCID: PMC4632802 DOI: 10.3390/ijms161025285] [Citation(s) in RCA: 46] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2015] [Revised: 10/10/2015] [Accepted: 10/12/2015] [Indexed: 12/29/2022] Open
Abstract
We present a combined environmental epidemiologic, genomic, and bioinformatics approach to identify: exposure of environmental chemicals with estrogenic activity; epidemiologic association between endocrine disrupting chemical (EDC) and health effects, such as, breast cancer or endometriosis; and gene-EDC interactions and disease associations. Human exposure measurement and modeling confirmed estrogenic activity of three selected class of environmental chemicals, polychlorinated biphenyls (PCBs), bisphenols (BPs), and phthalates. Meta-analysis showed that PCBs exposure, not Bisphenol A (BPA) and phthalates, increased the summary odds ratio for breast cancer and endometriosis. Bioinformatics analysis of gene-EDC interactions and disease associations identified several hundred genes that were altered by exposure to PCBs, phthalate or BPA. EDCs-modified genes in breast neoplasms and endometriosis are part of steroid hormone signaling and inflammation pathways. All three EDCs–PCB 153, phthalates, and BPA influenced five common genes—CYP19A1, EGFR, ESR2, FOS, and IGF1—in breast cancer as well as in endometriosis. These genes are environmentally and estrogen responsive, altered in human breast and uterine tumors and endometriosis lesions, and part of Mitogen Activated Protein Kinase (MAPK) signaling pathways in cancer. Our findings suggest that breast cancer and endometriosis share some common environmental and molecular risk factors.
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Abstract
Obesity is a leading modifiable risk factor for the development of several epithelial malignancies. In addition to increasing risk, obesity also confers worse prognosis for many cancers. Obesity represents an overall state of energy imbalance frequently associated with systemic effects including insulin resistance, altered hormone signaling, and high circulating levels of proinflammatory mediators. In addition to its systemic effects, obesity causes subclinical white adipose inflammation including increased tissue levels of proinflammatory mediators. Both local and systemic effects are likely to contribute to the development and progression of cancer. An understanding of the interplay between local and systemic alterations involved in the obesity-cancer link provides the basis for developing interventions aimed at mitigating the protumorigenic effects.
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Affiliation(s)
- Neil M Iyengar
- Memorial Sloan Kettering Cancer Center, New York, NY 10065; ,
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Gucalp A, Iyengar NM, Hudis CA, Dannenberg AJ. Targeting obesity-related adipose tissue dysfunction to prevent cancer development and progression. Semin Oncol 2015; 43:154-160. [PMID: 26970134 DOI: 10.1053/j.seminoncol.2015.09.012] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
The incidence of obesity, a leading modifiable risk factor for common solid tumors, is increasing. Effective interventions are needed to minimize the public health implications of obesity. Although the mechanisms linking increased adiposity to malignancy are incompletely understood, growing evidence points to complex interactions among multiple systemic and tissue-specific pathways including inflamed white adipose tissue. The metabolic and inflammatory consequences of white adipose tissue dysfunction collectively provide a plausible explanation for the link between overweight/obesity and carcinogenesis. Gaining a better understanding of these underlying molecular pathways and developing risk assessment tools that identify at-risk populations will be critical in implementing effective and novel cancer prevention and management strategies.
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Affiliation(s)
- Ayca Gucalp
- Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA; Department of Medicine, Weill Cornell Medical College, New York, NY, USA.
| | - Neil M Iyengar
- Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA; Department of Medicine, Weill Cornell Medical College, New York, NY, USA
| | - Clifford A Hudis
- Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA; Department of Medicine, Weill Cornell Medical College, New York, NY, USA
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Shao X, Guo Y, Xu X, Zheng Y, Wang J, Chen Z, Huang J, Huang P, Cai J, Wang X. The CYP19 RS4646 polymorphism IS related to the prognosis of stage I-II and operable stage III breast cancer. PLoS One 2015; 10:e0121535. [PMID: 25793413 PMCID: PMC4368615 DOI: 10.1371/journal.pone.0121535] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2014] [Accepted: 02/03/2015] [Indexed: 12/03/2022] Open
Abstract
Purpose Aromatase, encoded by the CYP19 gene, catalyzes the final step of the conversion of androgens to estrogens. Given the critical role of CYP19 in estrogen synthesis, the potential influence of CYP19 rs4646 polymorphism on breast cancer survival, deserves further study. Methods Genotyping for CYP19 rs4646 variants was performed on 406 Chinese women with stage I–II and operable stage III breast cancer. Associations were evaluated between CYP19 rs4646 genotypes and disease-free survival (DFS). Results In premenopausal patients, women who are homozygous for the minor allele (AA) have a longer DFS compared with those carrying the major allele (CC or AC) (87 months versus 48.7 months; Hazard ratio (HR) = 0.56, 95 % CI = 0.318-0.985, P = 0.041). These differences were further demonstrated by a multivariate analysis (HR = 0.456, 95 % CI = 0.249-0.836, P = 0.011). Conversely, the same variant (AA) was estimated to be associated with a poorer DFS in postmenopausal women (AA versus AC or CC: 13.7 months versus 56.3 months; HR = 2.758, 95 % CI = 1.432-5.313, P = 0.002). Furthermore, the differences were confirmed by the COX proportional hazards model (HR = 2.983, 95% CI =1.494-5.955, P = 0.002). Conclusions The present study indicates that CYP19 rs4646 polymorphism is related to DFS in early breast cancer and that the prognosis index of the homozygous for the minor allele (AA) may depend on menopause status. The findings are novel, if confirmed, rs4646 genotypes may provide useful information for routine management in breast cancer.
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Affiliation(s)
- Xiying Shao
- Department of Medical Oncology, The Affiliated Zhejiang Cancer Hospital of Zhejiang Chinese Medical University, Hangzhou, Zhejiang Province, China
| | - Yong Guo
- Department of Oncology, The First Affiliated Hospital of Zhejiang Traditional Chinese Medical University, Hangzhou, Zhejiang Province, China
| | - Xiaohong Xu
- Clinical laboratory, The Affiliated Zhejiang Cancer Hospital of Zhejiang Chinese Medical University, Hangzhou, Zhejiang Province, China
| | - Yabing Zheng
- Department of Medical Oncology, The Affiliated Zhejiang Cancer Hospital of Zhejiang Chinese Medical University, Hangzhou, Zhejiang Province, China
| | - Jiwen Wang
- Department of Oncology, Zhejiang Cancer Hospital, Hangzhou, Zhejiang Province, China
| | - Zhanhong Chen
- Department of Medical Oncology, The Affiliated Zhejiang Cancer Hospital of Zhejiang Chinese Medical University, Hangzhou, Zhejiang Province, China
| | - Jian Huang
- Department of Medical Oncology, The Affiliated Zhejiang Cancer Hospital of Zhejiang Chinese Medical University, Hangzhou, Zhejiang Province, China
| | - Ping Huang
- Department of Medical Oncology, The Affiliated Zhejiang Cancer Hospital of Zhejiang Chinese Medical University, Hangzhou, Zhejiang Province, China
| | - Jufen Cai
- Department of Medical Oncology, The Affiliated Zhejiang Cancer Hospital of Zhejiang Chinese Medical University, Hangzhou, Zhejiang Province, China
| | - Xiaojia Wang
- Department of Medical Oncology, The Affiliated Zhejiang Cancer Hospital of Zhejiang Chinese Medical University, Hangzhou, Zhejiang Province, China
- * E-mail:
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46
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Sun MY, Du HY, Zhu AN, Liang HY, de Garibay GR, Li FX, Li M, Yang XX. Genetic polymorphisms in estrogen-related genes and the risk of breast cancer among Han Chinese women. Int J Mol Sci 2015; 16:4121-35. [PMID: 25689428 PMCID: PMC4346947 DOI: 10.3390/ijms16024121] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2014] [Revised: 01/21/2015] [Accepted: 02/04/2015] [Indexed: 12/21/2022] Open
Abstract
Exposure to high levels of estrogen is considered an important risk factor for susceptibility to breast cancer. Common polymorphisms in genes that affect estrogen levels may be associated with breast cancer risk, but no comprehensive study has been performed among Han Chinese women. In the present study, 32 single-nucleotide polymorphisms (SNPs) in estrogen-related genes were genotyped using the MassARRAY IPLEX platform in 1076 Han Chinese women. Genotypic and allelic frequencies were compared between case and control groups. Unconditional logistic regression was used to assess the effects of SNPs on breast cancer risk. Associations were also evaluated for breast cancer subtypes stratified by estrogen receptor (ER) and progesterone receptor (PR) status. Case-control analysis showed a significant relation between heterozygous genotypes of rs700519 and rs2069522 and breast cancer risk (OR = 0.723, 95% CI = 0.541-0.965, p = 0.028 and OR = 1.500, 95% CI = 1.078-2.087, p = 0.016, respectively). Subgroup comparisons revealed that rs2446405 and rs17268974 were related to ER status, and rs130021 was associated with PR status. Our findings suggest that rs700519 and rs2069522 are associated with susceptibility to breast cancer among the Han Chinese population and have a cumulative effect with three other identified SNPs. Further genetic and functional studies are needed to identify additional SNPs, and to elucidate the underlying molecular mechanisms.
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Affiliation(s)
- Min-Ying Sun
- Guangzhou Center for Disease Control and Prevention, Guangzhou 510440, China.
| | - Hong-Yan Du
- School of Biotechnology, Southern Medical University, Guangzhou 510515, China.
| | - An-Na Zhu
- School of Biotechnology, Southern Medical University, Guangzhou 510515, China.
| | - Hui-Ying Liang
- Guangzhou Center for Disease Control and Prevention, Guangzhou 510440, China.
| | - Gorka Ruiz de Garibay
- Catalan Institute of Oncology, Bellvitge Institute for Biomedical Research, Barcelona 08908, Spain.
| | - Fen-Xia Li
- School of Biotechnology, Southern Medical University, Guangzhou 510515, China.
| | - Ming Li
- School of Biotechnology, Southern Medical University, Guangzhou 510515, China.
| | - Xue-Xi Yang
- School of Biotechnology, Southern Medical University, Guangzhou 510515, China.
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47
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Esquivel-Velázquez M, Ostoa-Saloma P, Palacios-Arreola MI, Nava-Castro KE, Castro JI, Morales-Montor J. The role of cytokines in breast cancer development and progression. J Interferon Cytokine Res 2015; 35:1-16. [PMID: 25068787 PMCID: PMC4291218 DOI: 10.1089/jir.2014.0026] [Citation(s) in RCA: 339] [Impact Index Per Article: 33.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2014] [Accepted: 05/23/2014] [Indexed: 12/12/2022] Open
Abstract
Cytokines are highly inducible, secretory proteins that mediate intercellular communication in the immune system. They are grouped into several protein families that are referred to as tumor necrosis factors, interleukins, interferons, and colony-stimulating factors. In recent years, it has become clear that some of these proteins as well as their receptors are produced in the organisms under physiological and pathological conditions. The exact initiation process of breast cancer is unknown, although several hypotheses have emerged. Inflammation has been proposed as an important player in tumor initiation, promotion, angiogenesis, and metastasis, all phenomena in which cytokines are prominent players. The data here suggest that cytokines play an important role in the regulation of both induction and protection in breast cancer. This knowledge could be fundamental for the proposal of new therapeutic approaches to particularly breast cancer and other cancer-related disorders.
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Affiliation(s)
- Marcela Esquivel-Velázquez
- Departamento de Inmunología, Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México, México City, México
| | - Pedro Ostoa-Saloma
- Departamento de Inmunología, Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México, México City, México
| | | | - Karen E. Nava-Castro
- Centro de Investigación Sobre Enfermedades Infecciosas, Instituto Nacional de Salud Pública, SSA, Cuernavaca, Morelos, México
| | - Julieta Ivonne Castro
- Centro de Investigación Sobre Enfermedades Infecciosas, Instituto Nacional de Salud Pública, SSA, Cuernavaca, Morelos, México
| | - Jorge Morales-Montor
- Departamento de Inmunología, Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México, México City, México
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To SQ, Knower KC, Cheung V, Simpson ER, Clyne CD. Transcriptional control of local estrogen formation by aromatase in the breast. J Steroid Biochem Mol Biol 2015; 145:179-86. [PMID: 24846828 DOI: 10.1016/j.jsbmb.2014.05.004] [Citation(s) in RCA: 35] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/24/2014] [Accepted: 05/11/2014] [Indexed: 12/11/2022]
Abstract
Aromatase is the critical enzyme that converts androgens to estrogens. It is frequently highly expressed in the tumour bearing breast of women diagnosed with estrogen receptor positive tumours, resulting in dramatically increased local estrogen production to drive tumour progression. Expression of aromatase is regulated primarily at the transcriptional level of its encoding gene CYP19A1, located on chromosome 15 of the human genome. A characteristic feature of CYP19A1 expression is its use of alternative promoters to regulate transcription in a tissue-specific manner. In breast cancer, the increase in aromatase expression is mediated via higher expression of the distal adipose-specific promoter I.4 and a switch to the preferential use of proximal promoters I.3 and II. This results in a net increase of CYP19A1 transcripts in tumour-bearing breast up to 3-4-fold higher than normal breast. Current aromatase inhibitors - whilst efficacious - exhibit significant side effects that reduce patient compliance. Understanding the transcription factors and signalling pathways that control aromatase expression will lead to opportunities to develop breast-specific inhibitors with an improved side-effects profile. This article is part of a Special Issue entitled 'Essential role of DHEA'.
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Affiliation(s)
- Sarah Q To
- Cancer Drug Discovery Laboratory, MIMR-PHI Institute of Medical Research, Clayton, Victoria 3168, Australia; Monash University, Clayton, Victoria 3168, Australia.
| | - Kevin C Knower
- Cancer Drug Discovery Laboratory, MIMR-PHI Institute of Medical Research, Clayton, Victoria 3168, Australia; Monash University, Clayton, Victoria 3168, Australia.
| | - Vanessa Cheung
- Cancer Drug Discovery Laboratory, MIMR-PHI Institute of Medical Research, Clayton, Victoria 3168, Australia; Monash University, Clayton, Victoria 3168, Australia
| | - Evan R Simpson
- Metabolism and Cancer Laboratory, MIMR-PHI Institute of Medical Research, Clayton, Victoria 3168, Australia; Monash University, Clayton, Victoria 3168, Australia
| | - Colin D Clyne
- Cancer Drug Discovery Laboratory, MIMR-PHI Institute of Medical Research, Clayton, Victoria 3168, Australia; Monash University, Clayton, Victoria 3168, Australia
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n-3 polyunsaturated fatty acids and mechanisms to mitigate inflammatory paracrine signaling in obesity-associated breast cancer. Nutrients 2014; 6:4760-93. [PMID: 25360510 PMCID: PMC4245562 DOI: 10.3390/nu6114760] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2014] [Revised: 10/08/2014] [Accepted: 10/10/2014] [Indexed: 02/06/2023] Open
Abstract
Globally, the prevalence of obesity is increasing which subsequently increases the risk of the development of obesity-related chronic diseases. Low-grade chronic inflammation and dysregulated adipose tissue inflammatory mediator/adipokine secretion are well-established in obesity, and these factors increase the risk of developing inflammation-associated cancer. Breast cancer is of particular interest given that increased inflammation within the subcutaneous mammary adipose tissue depot can alter the local tissue inflammatory microenvironment such that it resembles that of obese visceral adipose tissue. Therefore, in obese women with breast cancer, increased inflammatory mediators both locally and systemically can perpetuate inflammation-associated pro-carcinogenic signaling pathways, thereby increasing disease severity. Herein, we discuss some of these inflammation-associated pro-carcinogenic mechanisms of the combined obese breast cancer phenotype and offer evidence that dietary long chain n-3 polyunsaturated fatty acids (PUFA) may have utility in mitigating the severity of obesity-associated inflammation and breast cancer.
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50
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In subfertile couple, abdominal fat loss in men is associated with improvement of sperm quality and pregnancy: a case-series. PLoS One 2014; 9:e86300. [PMID: 24520319 PMCID: PMC3919721 DOI: 10.1371/journal.pone.0086300] [Citation(s) in RCA: 40] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2013] [Accepted: 12/08/2013] [Indexed: 12/13/2022] Open
Abstract
Background The impact of overweight among men of reproductive-age may affect fertility. Abdominal fat, more than body mass index, is an indicator of higher metabolic risk, which seems to be involved in decreasing sperm quality. This study aims to assess the relationship between abdominal fat and sperm DNA fragmentation and the effect of abdominal fat loss, among 6 men in subfertile couples. Methods Sperm DNA fragmentation, abdominal fat and metabolic and hormonal profiles were measured in the 6 men before and after dietary advices. Seminal oxidative stress and antioxidant markers were determined. Results After several months of a lifestyle program, all 6 men lost abdominal fat (patient 1: loss of 3 points of abdominal fat, patient 2: loss of 3 points, patient 3: loss of 2 points, patient 4: loss of 1 point, patient 5: loss of 4 points and patient 6: loss of 13 points). At the same time, their rate of sperm DNA fragmentation decreased: 9.5% vs 31%, 24% vs 43%, 18% vs 47%, 26.3% vs 66%, 25.4% vs 35% and 1.7% vs 25%. Also, an improvement in both metabolic (significant decrease in triglycerides and total cholesterol; p = 0.0139) and hormonal (significant increase in testosterone/oestradiol ratio; p = 0.0139) blood profiles was observed after following the lifestyle program. In seminal plasma, the amount of SOD2 has significantly increased (p = 0.0139) while in parallel carbonylated proteins have decreased. Furthermore, all spouses got pregnant. All pregnancies were brought to term. Conclusion This study shows specifically that sperm DNA fragmentation among men in subfertile couples could be affected by abdominal fat, but improvement of lifestyle factor may correct this alteration. The effect of specific abdominal fat loss on sperm quality needs further investigation. The reduction of oxidative stress may be a contributing factor.
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