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Hawazie A, Druce M. Breast Cancer Risk and Management in the Endocrine Clinic: A Comprehensive Review. Clin Endocrinol (Oxf) 2025. [PMID: 39905814 DOI: 10.1111/cen.15209] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/09/2024] [Revised: 12/30/2024] [Accepted: 01/19/2025] [Indexed: 02/06/2025]
Abstract
OBJECTIVE This review seeks to provide endocrine clinicians with a comprehensive analysis of breast cancer risk, diagnostic modalities and management strategies in women with endocrine disorders, with particular emphasis on the influence of metabolic factors such as diabetes and obesity, and the role of Menopausal Hormone Therapy (MHT). DESIGN The review examines a spectrum of endocrine disorders commonly encountered in clinical practice, including Multiple Endocrine Neoplasia Types 1 (MEN1), 2 (MEN2) and 4 (MEN4), Von Hippel-Lindau syndrome (VHL), Pheochromocytoma and Paraganglioma (PPGL), Acromegaly, Hyperprolactinaemia, Polycystic Ovary Syndrome (PCOS), Congenital Adrenal Hyperplasia (CAH), Turner Syndrome, alongside metabolic conditions such as diabetes and obesity and the effects of MHT. The review critically appraises each disorder's association with breast cancer risk, screening implications and therapeutic management. PATIENTS This analysis focuses on women with the aforementioned endocrine and metabolic disorders, assessing their specific breast cancer risk profiles, informed by the latest clinical evidence and molecular insights. MEASUREMENTS The review comprehensively evaluates current evidence-based approaches to screening, diagnostic accuracy and treatment in this patient cohort. Emphasis is placed on the metabolic derangements, hormonal influences and genetic predispositions that modulate breast cancer risk, providing disorder-specific recommendations for individualised care. RESULTS The findings indicate a significantly elevated breast cancer risk in patients with MEN1, necessitating early initiation of MRI screening by age 40. In MEN2, emerging evidence suggests that combining RET inhibitors with endocrine therapy may yield clinical benefits, although further research is needed to validate this approach. The breast cancer risk associated with MEN4 and VHL syndromes, while documented, remains less well-characterised, requiring further investigation. Diabetes and obesity are confirmed as major modifiable risk factors, particularly in postmenopausal women, where hyperinsulinemia and metabolic dysfunction contribute to increased incidence and poorer outcomes, notably in triple-negative breast cancer (TNBC). The role of MHT, particularly combined oestrogen-progestogen therapy, is strongly associated with increased breast cancer risk, particularly for hormone receptor-positive malignancies, necessitating cautious use and personalised treatment planning. In contrast, oestrogen-only MHT appears to confer a reduced risk in women post-hysterectomy. For patients with PCOS, CAH and Turner Syndrome, while definitive evidence of elevated breast cancer risk is lacking, individualised screening strategies and careful hormone therapy management remain essential due to the complex interplay of hormonal and metabolic factors. CONCLUSIONS The review highlights the need for personalised breast cancer screening and management protocols in women with endocrine and metabolic disorders. For high-risk groups such as MEN1 patients, early initiation of MRI screening is warranted. In women with diabetes and obesity, targeted interventions addressing hyperinsulinemia and metabolic dysfunction are critical to mitigating their increased cancer risk. The association between MHT and breast cancer underscores the importance of individualised risk stratification in hormone therapy administration, particularly in women with predisposing genetic or endocrine conditions. Enhanced surveillance tailored to the unique risk profiles of endocrine disorder patients will facilitate early detection and improve clinical outcomes. However, further large-scale studies are necessary to refine these associations and develop robust, evidence-based guidelines.
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Affiliation(s)
- Arie Hawazie
- Centre for Endocrinology, Queen Mary University, London, UK
| | - Maralyn Druce
- Centre for Endocrinology, Queen Mary University, London, UK
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Wang X, Bao H, Huang YC, Barua A, Lai CM, Sun J, Zhou Y, Cong F, Gong S, Chang CH, Deng WM. Sex-dimorphic tumor growth is regulated by tumor microenvironmental and systemic signals. SCIENCE ADVANCES 2024; 10:eads4229. [PMID: 39642218 PMCID: PMC11623276 DOI: 10.1126/sciadv.ads4229] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/13/2024] [Accepted: 11/01/2024] [Indexed: 12/08/2024]
Abstract
Tumor growth and progression involve coordinated regulation by internal, microenvironmental, and systemic signals and often display conspicuous sexual dimorphism. The mechanisms governing the integration and coordination of these signals, along with their sex-based differences, remain largely unknown. Using a Drosophila tumor model originating from nonreproductive tissue, we show that female-biased tumor growth involves multifaceted communications among tumor cells, hemocytes, and neuroendocrine insulin-producing cells (IPCs). Notch-active tumor cells recruit hemocytes carrying the tumor necrosis factor-α (TNF-α) homolog Eiger to the tumor microenvironment (TME), activating the c-Jun N-terminal kinase (JNK) pathway in tumor cells, instigating the sexually dimorphic up-regulation of cytokine Unpaired 2 (Upd2). Upd2, in turn, exerts a distal influence by modulating the release of a Drosophila insulin-like peptide (Dilp2) from IPCs. Dilp2 then activates the insulin signaling in the tumor, thereby fostering sexual-dimorphic tumor growth. Together, these findings reveal a relay mechanism involving the TME and systemic signals that collectively control the sexual dimorphism of tumor growth.
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Affiliation(s)
- Xianfeng Wang
- Department of Biochemistry and Molecular Biology, Tulane University School of Medicine, Louisiana Cancer Research Center, New Orleans, LA 70112, USA
| | - Hongcun Bao
- Department of Biochemistry and Molecular Biology, Tulane University School of Medicine, Louisiana Cancer Research Center, New Orleans, LA 70112, USA
| | - Yi-Chun Huang
- Department of Biochemistry and Molecular Biology, Tulane University School of Medicine, Louisiana Cancer Research Center, New Orleans, LA 70112, USA
| | - Anindita Barua
- Department of Biochemistry and Molecular Biology, Tulane University School of Medicine, Louisiana Cancer Research Center, New Orleans, LA 70112, USA
| | | | - Jie Sun
- Department of Biochemistry and Molecular Biology, Tulane University School of Medicine, Louisiana Cancer Research Center, New Orleans, LA 70112, USA
| | - Youfang Zhou
- Department of Biochemistry and Molecular Biology, Tulane University School of Medicine, Louisiana Cancer Research Center, New Orleans, LA 70112, USA
| | - Fei Cong
- Department of Biochemistry and Molecular Biology, Tulane University School of Medicine, Louisiana Cancer Research Center, New Orleans, LA 70112, USA
| | | | | | - Wu-Min Deng
- Department of Biochemistry and Molecular Biology, Tulane University School of Medicine, Louisiana Cancer Research Center, New Orleans, LA 70112, USA
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Podmore L, Poloz Y, Iorio C, Mouaaz S, Nixon K, Smirnov P, McDonnell B, Lam S, Zhang B, Tharmapalan P, Sarkar S, Vyas F, Ennis M, Dowling R, Stambolic V. Insulin receptor loss impairs mammary tumorigenesis in mice. Cell Rep 2023; 42:113251. [PMID: 37913774 DOI: 10.1016/j.celrep.2023.113251] [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: 09/30/2022] [Revised: 09/05/2023] [Accepted: 09/27/2023] [Indexed: 11/03/2023] Open
Abstract
Breast cancer (BC) prognosis and outcome are adversely affected by obesity. Hyperinsulinemia, common in the obese state, is associated with higher risk of death and recurrence in BC. Up to 80% of BCs overexpress the insulin receptor (INSR), which correlates with worse prognosis. INSR's role in mammary tumorigenesis was tested by generating MMTV-driven polyoma middle T (PyMT) and ErbB2/Her2 BC mouse models, respectively, with coordinate mammary epithelium-restricted deletion of INSR. In both models, deletion of either one or both copies of INSR leads to a marked delay in tumor onset and burden. Longitudinal phenotypic characterization of mouse tumors and cells reveals that INSR deletion affects tumor initiation, not progression and metastasis. INSR upholds a bioenergetic phenotype in non-transformed mammary epithelial cells, independent of its kinase activity. Similarity of phenotypes elicited by deletion of one or both copies of INSR suggest a dose-dependent threshold for INSR impact on mammary tumorigenesis.
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Affiliation(s)
- Lauren Podmore
- Department of Medical Biophysics, University of Toronto, Princess Margaret Cancer Research Tower, Toronto, ON M5G 1L7, Canada
| | - Yekaterina Poloz
- Princess Margaret Cancer Centre, University Health Network, Princess Margaret Cancer Research Tower, Toronto, ON M5G 1L7, Canada
| | - Catherine Iorio
- Princess Margaret Cancer Centre, University Health Network, Princess Margaret Cancer Research Tower, Toronto, ON M5G 1L7, Canada
| | - Samar Mouaaz
- Princess Margaret Cancer Centre, University Health Network, Princess Margaret Cancer Research Tower, Toronto, ON M5G 1L7, Canada
| | - Kevin Nixon
- Princess Margaret Cancer Centre, University Health Network, Princess Margaret Cancer Research Tower, Toronto, ON M5G 1L7, Canada
| | - Petr Smirnov
- Department of Medical Biophysics, University of Toronto, Princess Margaret Cancer Research Tower, Toronto, ON M5G 1L7, Canada
| | - Brianna McDonnell
- Department of Medical Biophysics, University of Toronto, Princess Margaret Cancer Research Tower, Toronto, ON M5G 1L7, Canada
| | - Sonya Lam
- Princess Margaret Cancer Centre, University Health Network, Princess Margaret Cancer Research Tower, Toronto, ON M5G 1L7, Canada
| | - Bowen Zhang
- Department of Medical Biophysics, University of Toronto, Princess Margaret Cancer Research Tower, Toronto, ON M5G 1L7, Canada
| | - Pirashaanthy Tharmapalan
- Department of Medical Biophysics, University of Toronto, Princess Margaret Cancer Research Tower, Toronto, ON M5G 1L7, Canada
| | - Soumili Sarkar
- Department of Medical Biophysics, University of Toronto, Princess Margaret Cancer Research Tower, Toronto, ON M5G 1L7, Canada
| | - Foram Vyas
- Department of Medical Biophysics, University of Toronto, Princess Margaret Cancer Research Tower, Toronto, ON M5G 1L7, Canada
| | | | - Ryan Dowling
- Princess Margaret Cancer Centre, University Health Network, Princess Margaret Cancer Research Tower, Toronto, ON M5G 1L7, Canada
| | - Vuk Stambolic
- Department of Medical Biophysics, University of Toronto, Princess Margaret Cancer Research Tower, Toronto, ON M5G 1L7, Canada; Princess Margaret Cancer Centre, University Health Network, Princess Margaret Cancer Research Tower, Toronto, ON M5G 1L7, Canada.
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4
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Mak LY, Hui RWH, Lee CH, Mao X, Cheung KS, Wong DKH, Lui DTW, Fung J, Yuen MF, Seto WK. Glycemic burden and the risk of adverse hepatic outcomes in patients with chronic hepatitis B with type 2 diabetes. Hepatology 2023; 77:606-618. [PMID: 36130882 DOI: 10.1002/hep.32716] [Citation(s) in RCA: 30] [Impact Index Per Article: 15.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/04/2022] [Revised: 07/27/2022] [Accepted: 08/08/2022] [Indexed: 02/06/2023]
Abstract
BACKGROUND AND AIMS Type 2 diabetes (T2D) is common among patients with chronic hepatitis B infection (CHB) and has been associated with increased risk of carcinogenesis, including HCC. We investigated factors associated with HCC and fibrosis progression among patients with CHB with T2D (CHB+T2D). APPROACH AND RESULTS Chinese patients with CHB were prospectively recruited for the incidence of HCC and fibrosis progression defined by transient elastography. Among patients with CHB+T2D, glycemic control was assessed by mean glycated hemoglobin (HbA1c) and HbA1c variability determined using HbA1c measurements in the 5 years preceding recruitment. A total of 2330 patients with CHB were recruited (mean age 54.6 ±11.8 years old, 55.5% male, 57.9% antiviral-treated), with 671 (28.8%) having CHB+T2D (mean T2D duration 7.2 ± 4.6 years, mean HbA1c 7.2 ± 0.9%). T2D was independently associated with HCC (HR 2.080, 95% CI 1.343-3.222) and fibrosis progression (OR 4.305, 95% CI 3.416-5.424) in the overall cohort. In patients with CHB+T2D, factors reflecting glycemic burden (T2D duration [HR 1.107, 95% CI 1.023-1.198]), mean HbA1c (HR 1.851, 95% CI 1.026-3.339), time reaching target HbA1c (HbA1c-TRT; HR 0.978, 95% CI 0.957-0.999), liver stiffness (HR 1.041-1.043), and smoking (HR 2.726-3.344) were independently associated with HCC (all p < 0.05), but not HbA1c variability or controlled attenuation parameter. The same glycemic burden-related factors (T2D duration, mean HbA1c, and HbA1c-TRT), in addition to baseline fasting glucose, baseline HbA1c, AST and antiviral therapy, were independently associated with fibrosis progression at 3 years. CONCLUSIONS High glycemic burden was associated with HCC development and fibrosis progression among patients with CHB+T2D, highlighting the importance of glycemic control in reducing liver-related complications.
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Affiliation(s)
- Lung-Yi Mak
- Department of Medicine , Queen Mary Hospital, The University of Hong Kong , Hong Kong.,State Key Laboratory of Liver Research , The University of Hong Kong , Hong Kong
| | - Rex Wan-Hin Hui
- Department of Medicine , Queen Mary Hospital, The University of Hong Kong , Hong Kong
| | - Chi-Ho Lee
- Department of Medicine , Queen Mary Hospital, The University of Hong Kong , Hong Kong
| | - XianHua Mao
- Department of Medicine , Queen Mary Hospital, The University of Hong Kong , Hong Kong
| | - Ka-Shing Cheung
- Department of Medicine , Queen Mary Hospital, The University of Hong Kong , Hong Kong.,Department of Medicine , The University of Hong Kong-Shenzhen Hospital , Shenzhen , China
| | - Danny Ka-Ho Wong
- Department of Medicine , Queen Mary Hospital, The University of Hong Kong , Hong Kong.,State Key Laboratory of Liver Research , The University of Hong Kong , Hong Kong
| | - David Tak-Wai Lui
- Department of Medicine , Queen Mary Hospital, The University of Hong Kong , Hong Kong
| | - James Fung
- Department of Medicine , Queen Mary Hospital, The University of Hong Kong , Hong Kong.,State Key Laboratory of Liver Research , The University of Hong Kong , Hong Kong
| | - Man-Fung Yuen
- Department of Medicine , Queen Mary Hospital, The University of Hong Kong , Hong Kong.,State Key Laboratory of Liver Research , The University of Hong Kong , Hong Kong
| | - Wai-Kay Seto
- Department of Medicine , Queen Mary Hospital, The University of Hong Kong , Hong Kong.,State Key Laboratory of Liver Research , The University of Hong Kong , Hong Kong.,Department of Medicine , The University of Hong Kong-Shenzhen Hospital , Shenzhen , China
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Chintamani, Tandon M, Ghosh J. Breast Cancer with Associated Problems. Breast Cancer 2022. [DOI: 10.1007/978-981-16-4546-4_24] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
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Scully T, Ettela A, LeRoith D, Gallagher EJ. Obesity, Type 2 Diabetes, and Cancer Risk. Front Oncol 2021; 10:615375. [PMID: 33604295 PMCID: PMC7884814 DOI: 10.3389/fonc.2020.615375] [Citation(s) in RCA: 108] [Impact Index Per Article: 27.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2020] [Accepted: 12/09/2020] [Indexed: 12/12/2022] Open
Abstract
Obesity and type 2 diabetes have both been associated with increased cancer risk and are becoming increasingly prevalent. Metabolic abnormalities such as insulin resistance and dyslipidemia are associated with both obesity and type 2 diabetes and have been implicated in the obesity-cancer relationship. Multiple mechanisms have been proposed to link obesity and diabetes with cancer progression, including an increase in insulin/IGF-1 signaling, lipid and glucose uptake and metabolism, alterations in the profile of cytokines, chemokines, and adipokines, as well as changes in the adipose tissue directly adjacent to the cancer sites. This review aims to summarize and provide an update on the epidemiological and mechanistic evidence linking obesity and type 2 diabetes with cancer, focusing on the roles of insulin, lipids, and adipose tissue.
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Affiliation(s)
- Tiffany Scully
- Division of Endocrinology, Diabetes and Bone Disease, Icahn School of Medicine at Mount Sinai, New York City, NY, United States
| | - Abora Ettela
- Division of Endocrinology, Diabetes and Bone Disease, Icahn School of Medicine at Mount Sinai, New York City, NY, United States
| | - Derek LeRoith
- Division of Endocrinology, Diabetes and Bone Disease, Icahn School of Medicine at Mount Sinai, New York City, NY, United States
- Tisch Cancer Institute at Mount Sinai, Icahn School of Medicine at Mount Sinai, New York City, NY, United States
| | - Emily Jane Gallagher
- Division of Endocrinology, Diabetes and Bone Disease, Icahn School of Medicine at Mount Sinai, New York City, NY, United States
- Tisch Cancer Institute at Mount Sinai, Icahn School of Medicine at Mount Sinai, New York City, NY, United States
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7
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Das M, Ellies LG, Kumar D, Sauceda C, Oberg A, Gross E, Mandt T, Newton IG, Kaur M, Sears DD, Webster NJG. Time-restricted feeding normalizes hyperinsulinemia to inhibit breast cancer in obese postmenopausal mouse models. Nat Commun 2021; 12:565. [PMID: 33495474 PMCID: PMC7835248 DOI: 10.1038/s41467-020-20743-7] [Citation(s) in RCA: 48] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2019] [Accepted: 12/04/2020] [Indexed: 01/30/2023] Open
Abstract
Accumulating evidence indicates that obesity with its associated metabolic dysregulation, including hyperinsulinemia and aberrant circadian rhythms, increases the risk for a variety of cancers including postmenopausal breast cancer. Caloric restriction can ameliorate the harmful metabolic effects of obesity and inhibit cancer progression but is difficult to implement and maintain outside of the clinic. In this study, we aim to test a time-restricted feeding (TRF) approach on mouse models of obesity-driven postmenopausal breast cancer. We show that TRF abrogates the obesity-enhanced mammary tumor growth in two orthotopic models in the absence of calorie restriction or weight loss. TRF also reduces breast cancer metastasis to the lung. Furthermore, TRF delays tumor initiation in a transgenic model of mammary tumorigenesis prior to the onset of obesity. Notably, TRF increases whole-body insulin sensitivity, reduces hyperinsulinemia, restores diurnal gene expression rhythms in the tumor, and attenuates tumor growth and insulin signaling. Importantly, inhibition of insulin secretion with diazoxide mimics TRF whereas artificial elevation of insulin through insulin pumps implantation reverses the effect of TRF, suggesting that TRF acts through modulating hyperinsulinemia. Our data suggest that TRF is likely to be effective in breast cancer prevention and therapy.
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Affiliation(s)
- Manasi Das
- VA San Diego Healthcare System, San Diego, CA, USA
- Department of Medicine, Division of Endocrinology and Metabolism, University of California San Diego, La Jolla, CA, USA
| | - Lesley G Ellies
- Department of Pathology, University of California San Diego, La Jolla, CA, USA
- Moores Cancer Center, University of California, San Diego, La Jolla, CA, USA
| | - Deepak Kumar
- VA San Diego Healthcare System, San Diego, CA, USA
- Department of Medicine, Division of Endocrinology and Metabolism, University of California San Diego, La Jolla, CA, USA
| | - Consuelo Sauceda
- VA San Diego Healthcare System, San Diego, CA, USA
- Department of Medicine, Division of Endocrinology and Metabolism, University of California San Diego, La Jolla, CA, USA
| | - Alexis Oberg
- VA San Diego Healthcare System, San Diego, CA, USA
| | - Emilie Gross
- VA San Diego Healthcare System, San Diego, CA, USA
- Department of Medicine, Division of Endocrinology and Metabolism, University of California San Diego, La Jolla, CA, USA
| | - Tyler Mandt
- Department of Radiology, University of California, San Diego, La Jolla, CA, USA
| | - Isabel G Newton
- Department of Radiology, University of California, San Diego, La Jolla, CA, USA
| | - Mehak Kaur
- Department of Medicine, Division of Endocrinology and Metabolism, University of California San Diego, La Jolla, CA, USA
| | - Dorothy D Sears
- Department of Medicine, Division of Endocrinology and Metabolism, University of California San Diego, La Jolla, CA, USA
- Moores Cancer Center, University of California, San Diego, La Jolla, CA, USA
- Department of Family Medicine and Public Health, Division of Preventive Medicine, University of California San Diego, La Jolla, CA, USA
- College of Health Solutions, Arizona State University, Phoenix, AZ, USA
| | - Nicholas J G Webster
- VA San Diego Healthcare System, San Diego, CA, USA.
- Department of Medicine, Division of Endocrinology and Metabolism, University of California San Diego, La Jolla, CA, USA.
- Moores Cancer Center, University of California, San Diego, La Jolla, CA, USA.
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8
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Disrupting Insulin and IGF Receptor Function in Cancer. Int J Mol Sci 2021; 22:ijms22020555. [PMID: 33429867 PMCID: PMC7827299 DOI: 10.3390/ijms22020555] [Citation(s) in RCA: 29] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2020] [Revised: 12/29/2020] [Accepted: 01/06/2021] [Indexed: 02/07/2023] Open
Abstract
The insulin and insulin-like growth factor (IGF) system plays an important role in regulating normal cell proliferation and survival. However, the IGF system is also implicated in many malignancies, including breast cancer. Preclinical studies indicate several IGF blocking approaches, such as monoclonal antibodies and tyrosine kinase inhibitors, have promising therapeutic potential for treating diseases. Uniformly, phase III clinical trials have not shown the benefit of blocking IGF signaling compared to standard of care arms. Clinical and laboratory data argue that targeting Type I IGF receptor (IGF1R) alone may be insufficient to disrupt this pathway as the insulin receptor (IR) may also be a relevant cancer target. Here, we review the well-studied role of the IGF system in regulating malignancies, the limitations on the current strategies of blocking the IGF system in cancer, and the potential future directions for targeting the IGF system.
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Kariagina A, Morozova E, Hoshyar R, Aupperlee MD, Borin MA, Haslam SZ, Schwartz RC. Benzophenone-3 promotion of mammary tumorigenesis is diet-dependent. Oncotarget 2020; 11:4465-4478. [PMID: 33400736 PMCID: PMC7721615 DOI: 10.18632/oncotarget.27831] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2020] [Accepted: 11/20/2020] [Indexed: 11/25/2022] Open
Abstract
Benzophenone-3 is a putative endocrine disrupting chemical and common ingredient in sunscreens. The potential of endocrine disrupting chemicals to act as agonists or antagonists in critical hormonally regulated processes, such as mammary gland development and mammary tumorigenesis, demands evaluation of its potential in promoting breast cancer. This study identifies the effects of BP-3 on mammary tumorigenesis with high-fat diet during puberty versus adulthood in Trp53-null transplant BALB/c mice. Benzophenone-3 exposure yielded levels in urine similar to humans subjected to heavy topical sunscreen exposure. Benzophenone-3 was protective for epithelial tumorigenesis in mice fed lifelong low-fat diet, while promotional for epithelial tumorigenesis in mice fed adult high-fat diet. Benzophenone-3 increased tumor cell proliferation, decreased tumor cell apoptosis, and increased tumor vascularity dependent on specific dietary regimen and tumor histopathology. Even in instances of an ostensibly protective effect, other parameters suggest greater risk. Although benzophenone-3 seemed protective on low-fat diet, spindle cell tumors arising in these mice showed increased proliferation and decreased apoptosis. This points to a need for further studies of benzophenone-3 in both animal models and humans as a potential breast cancer risk factor, as well as a more general need to evaluate endocrine disrupting chemicals in varying dietary contexts.
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Affiliation(s)
- Anastasia Kariagina
- Breast Cancer and the Environment Research Program, Department of Microbiology and Molecular Genetics, Michigan State University, East Lansing, MI, USA
| | - Elena Morozova
- Breast Cancer and the Environment Research Program, Department of Microbiology and Molecular Genetics, Michigan State University, East Lansing, MI, USA
| | - Reyhane Hoshyar
- Breast Cancer and the Environment Research Program, Department of Microbiology and Molecular Genetics, Michigan State University, East Lansing, MI, USA
| | - Mark D. Aupperlee
- Breast Cancer and the Environment Research Program, Department of Microbiology and Molecular Genetics, Michigan State University, East Lansing, MI, USA
| | - Mitchell A. Borin
- Breast Cancer and the Environment Research Program, Department of Microbiology and Molecular Genetics, Michigan State University, East Lansing, MI, USA
| | - Sandra Z. Haslam
- Breast Cancer and the Environment Research Program, Department of Physiology, Michigan State University, East Lansing, MI, USA
| | - Richard C. Schwartz
- Breast Cancer and the Environment Research Program, Department of Microbiology and Molecular Genetics, Michigan State University, East Lansing, MI, USA
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10
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Zhou W, Jiang R, Wang Y, Li Y, Sun Z, Zhao H. hsa_circ_001653 up-regulates NR6A1 expression and elicits gastric cancer progression by binding to microRNA-377. Exp Physiol 2020; 105:2141-2153. [PMID: 33006200 DOI: 10.1113/ep088399] [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] [Received: 12/17/2019] [Accepted: 09/29/2020] [Indexed: 12/21/2022]
Abstract
NEW FINDINGS What is the central question of this study? Does hsa_circ_001653 influence the development of gastric cancer (GC) and if so how? What is the main finding and its importance? Bioinformatics analysis revealed the presence of differentially expressed hsa_circ_001653 in GC and adjacent normal tissues, and this was strongly related to the pathology of patients with GC. Knockdown of hsa_circ_001653 suppressed the proliferation, invasion and migration of GC cells, while inducing cell apoptosis via miR-377-mediated NR6A1 inhibition. The effect of hsa_circ_001653 and miR-377 on tumour growth in GC was further confirmed in vivo. ABSTRACT Gastric cancer (GC) is one of the leading causes of human mortality through malignant tumours. Circular RNAs (circRNAs) have been identified as binding to microRNAs (miRNAs) to modulate the progression of tumours. This study explores the role of hsa_circ_001653, a newly identified circRNA, in the development of GC. hsa_circ_001653 expression was measured in 86 paired normal and tumour tissues surgically resected from GC patients. Cross-talk between hsa_circ_001653 and microRNA-377 (miR-377)/nuclear receptor subfamily 6, group A, member 1 (NR6A1) was assessed using bioinformatics analysis, dual-luciferase reporter assay, Ago2 immunoprecipitation and western blot analysis. A series of functional experiments were carried out to elucidate the role of hsa_circ_001653 in GC cell proliferation, invasion, migration and apoptosis, and its underlying molecular mechanisms. Nude mice were inoculated with GC cells for in vivo analysis. hsa_circ_001653 was found to be an up-regulated circRNA in GC tissues and cells. Down-regulation of hsa_circ_001653 inhibited GC cell proliferation, migration and invasion, while stimulating cell apoptosis. hsa_circ_001653 was found to bind to miR-377, which targeted NR6A1 and repressed its expression. Inhibition of miR-377 and overexpression of NR6A1 restored the proliferation, migration and invasion in GC cells lacking hsa_circ_001653. Furthermore, inhibition of hsa_circ_001653 attenuated tumour growth in nude mice inoculated with GC cells. Collectively, the demonstration that hsa_circ_001653 exerts its anticancer effects by regulating the miR-377-NR6A1 axis increases our understanding of gastric cancer pathophysiology. The findings uncover new potential therapeutic targets for GC.
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Affiliation(s)
- Wuyuan Zhou
- Department of Hepatopancreatobillary Surgery, Xuzhou Cancer Hospital, Xuzhou, China
| | - Rongke Jiang
- Department of Oncology, Xuzhou Cancer Hospital, Xuzhou, China
| | - Yu Wang
- Department of General Surgery, Xuzhou Cancer Hospital, Xuzhou, China
| | - Yanfang Li
- Department of Oncology, Xuzhou Cancer Hospital, Xuzhou, China
| | - Ziqian Sun
- Department of Oncology, Xuzhou Cancer Hospital, Xuzhou, China
| | - Hongying Zhao
- Department of Oncology, Xuzhou Cancer Hospital, Xuzhou, China
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Abstract
Elevated circulating insulin levels are frequently observed in the setting of obesity and early type 2 diabetes, as a result of insensitivity of metabolic tissues to the effects of insulin. Higher levels of circulating insulin have been associated with increased cancer risk and progression in epidemiology studies. Elevated circulating insulin is believed to be a major factor linking obesity, diabetes and cancer. With the development of targeted cancer therapies, insulin signalling has emerged as a mechanism of therapeutic resistance. Although metabolic tissues become insensitive to insulin in the setting of obesity, a number of mechanisms allow cancer cells to maintain their ability to respond to insulin. Significant progress has been made in the past decade in understanding the insulin receptor and its signalling pathways in cancer, and a number of lessons have been learnt from therapeutic failures. These discoveries have led to numerous clinical trials that have aimed to reduce the levels of circulating insulin and to abrogate insulin signalling in cancer cells. With the rising prevalence of obesity and diabetes worldwide, and the realization that hyperinsulinaemia may contribute to therapeutic failures, it is essential to understand how insulin and insulin receptor signalling promote cancer progression.
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Affiliation(s)
- Emily J Gallagher
- Division of Endocrinology, Diabetes and Bone Diseases, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
- The Tisch Cancer Institute at Mount Sinai, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
| | - Derek LeRoith
- Division of Endocrinology, Diabetes and Bone Diseases, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- The Tisch Cancer Institute at Mount Sinai, Icahn School of Medicine at Mount Sinai, New York, NY, USA
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Vigneri R, Sciacca L, Vigneri P. Rethinking the Relationship between Insulin and Cancer. Trends Endocrinol Metab 2020; 31:551-560. [PMID: 32600959 DOI: 10.1016/j.tem.2020.05.004] [Citation(s) in RCA: 47] [Impact Index Per Article: 9.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/08/2019] [Revised: 03/20/2020] [Accepted: 05/13/2020] [Indexed: 12/14/2022]
Abstract
In addition to being a major metabolic hormone, insulin is also a growth factor with a mitogenic effect on all cells, more marked in malignant cells that often overexpress the insulin receptor. In patients with metabolic diseases characterized by hyperinsulinemia (obesity, type 2 diabetes, and metabolic syndrome), the incidence of several types of cancer is increased, as is cancer-related mortality. Because of the worldwide growing prevalence of metabolic diseases and the diffuse use of insulin and its analogs for treating diabetes, the relationship between insulin and cancer has become a clinically relevant issue. Clinical studies have not clarified the degree to which hyperinsulinemia can influence cancer occurrence and prognosis. To better understand this issue, an improved scientific approach is required, with more careful consideration of the mechanisms related to hyperinsulinemia and carcinogenesis.
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Affiliation(s)
- R Vigneri
- Endocrinology, Department of Clinical and Experimental Medicine, University of Catania, Garibaldi-Nesima Medical Center, Catania, Italy.
| | - L Sciacca
- Endocrinology, Department of Clinical and Experimental Medicine, University of Catania, Garibaldi-Nesima Medical Center, Catania, Italy
| | - P Vigneri
- Center of Experimental Oncology and Hematology, Department of Clinical and Experimental Medicine, University of Catania, A.O.U. Policlinico Vittorio-Emanuele, Catania, Italy
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13
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Pleiotropic effects of anti-diabetic drugs: A comprehensive review. Eur J Pharmacol 2020; 884:173349. [PMID: 32650008 DOI: 10.1016/j.ejphar.2020.173349] [Citation(s) in RCA: 21] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2020] [Revised: 06/24/2020] [Accepted: 07/03/2020] [Indexed: 12/18/2022]
Abstract
Diabetes mellitus characterized by hyperglycaemia presents an array of comorbidities such as cardiovascular and renal failure, dyslipidemia, and cognitive impairments. Populations above the age of 60 are in an urgent need of effective therapies to deal with the complications associated with diabetes mellitus. Widely used anti-diabetic drugs have good safety profiles and multiple reports indicate their pleiotropic effects in diabetic patients or models. This review has been written with the objective of identifying the widely-marketed anti-diabetic drugs which can be efficiently repurposed for the treatment of other diseases or disorders. It is an updated, comprehensive review, describing the protective role of various classes of anti-diabetic drugs in mitigating the macro and micro vascular complications of diabetes mellitus, and differentiating these drugs on the basis of their mode of action. Notably, metformin, the anti-diabetic drug most commonly explored for cancer therapy, has also exhibited some antimicrobial effects. Unlike class specific effects, few instances of drug specific effects in managing cardiovascular complications have also been reported. A major drawback is that the pleiotropic effects of anti-diabetic drugs have been mostly investigated only in diabetic patients. Thus, for effective repurposing, more clinical trials devoted to analyse the effects of anti-diabetic drugs in patients irrespective of their diabetic condition, are required.
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14
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Sundaram S, Yan L. Adipose monocyte chemotactic protein-1 deficiency reduces high-fat diet-enhanced mammary tumorigenesis in MMTV-PyMT mice. J Nutr Biochem 2020; 77:108313. [PMID: 31837540 DOI: 10.1016/j.jnutbio.2019.108313] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2019] [Revised: 10/16/2019] [Accepted: 11/25/2019] [Indexed: 01/24/2023]
Abstract
Monocyte chemotactic protein-1 (MCP-1) is an adipokine with demonstrated carcinogenic potential. However, there is a lack of evidence whether adipose-produced MCP-1 contributes to breast cancer. We tested the hypothesis that adipose-produced MCP-1 contributes to mammary tumorigenesis in this study. In a breast cancer model of mouse mammary tumor virus-polyomavirus middle T-antigen (MMTV-PyMT), mice with or without adipose MCP-1 knockout [designated as Mcp-1-/- or wild-type (WT)] were fed the standard AIN93G diet (16% of energy from soybean oil) or a high-fat diet (HFD, 45% of energy from soybean oil). Adipose MCP-1 knockout reduced Mcp-1 expression in adipose tissue and concentrations of MCP-1 in plasma. Mcp-1-/- mice fed the HFD had less body fat than their WT counterparts. Adipose MCP-1 knockout attenuated HFD-enhanced mammary tumorigenesis, evidenced by lower mammary tumor volume. Furthermore, Mcp-1-/- mice, regardless of diet, had a longer tumor latency and less tumor weight than WT mice. When fed the HFD, Mcp-1-/- mice, compared to WT mice, exhibited lower concentrations of insulin, leptin, resistin, vascular endothelial growth factor and hepatic growth factor in plasma. In summary, adipose MCP-1 deficiency attenuated HFD-enhanced MMTV-PyMT mammary tumorigenesis. This attenuation can be attributed to less body adiposity, improvement in insulin sensitivity and down-regulation in protumorigenic inflammation cytokines and angiogenic factors in Mcp-1-/- mice. It concludes that adipose-produced MCP-1 contributes to mammary tumorigenesis in the MMTV-PyMT mouse model.
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Affiliation(s)
- Sneha Sundaram
- U.S. Department of Agriculture Agricultural Research Service, Grand Forks Human Nutrition Research Center, Grand Forks, ND 58203, USA.
| | - Lin Yan
- U.S. Department of Agriculture Agricultural Research Service, Grand Forks Human Nutrition Research Center, Grand Forks, ND 58203, USA.
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15
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Deng Q, Hu H, Yu X, Liu S, Wang L, Chen W, Zhang C, Zeng Z, Cao Y, Xu-Monette ZY, Li L, Zhang M, Rosenfeld S, Bao S, Hsi E, Young KH, Lu Z, Li Y. Tissue-specific microRNA expression alters cancer susceptibility conferred by a TP53 noncoding variant. Nat Commun 2019; 10:5061. [PMID: 31699989 PMCID: PMC6838078 DOI: 10.1038/s41467-019-13002-x] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2019] [Accepted: 10/16/2019] [Indexed: 12/15/2022] Open
Abstract
A noncoding polymorphism (rs78378222) in TP53, carried by scores of millions of people, was previously associated with moderate risk of brain tumors and other neoplasms. We find a positive association between this variant and soft tissue sarcoma. In sharp contrast, it is protective against breast cancer. We generated a mouse line carrying this variant and found that it accelerates spontaneous tumorigenesis and glioma development, but strikingly, delays mammary tumorigenesis. The variant creates a miR-382-5p targeting site and compromises a miR-325-3p site. Their differential expression results in p53 downregulation in the brain, but p53 upregulation in the mammary gland of polymorphic mice compared to that of wild-type littermates. Thus, this variant is at odds with Li-Fraumeni Syndrome mutants in breast cancer predisposition yet consistent in glioma predisposition. Our findings elucidate an underlying mechanism of cancer susceptibility that is conferred by genetic variation and yet altered by microRNA expression.
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Affiliation(s)
- Qipan Deng
- Department of Medicine, Section of Epidemiology and Population Sciences, Baylor College of Medicine, Houston, TX, USA
- Department of Cancer Biology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA
| | - Hui Hu
- Department of Cancer Biology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA
- Department of Medical Laboratory, Central Hospital of Wuhan, Wuhan, China
| | - Xinfang Yu
- Department of Medicine, Section of Epidemiology and Population Sciences, Baylor College of Medicine, Houston, TX, USA
- Department of Cancer Biology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA
| | - Shuanglin Liu
- Department of Medicine, Section of Epidemiology and Population Sciences, Baylor College of Medicine, Houston, TX, USA
- Department of Cancer Biology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA
| | - Lei Wang
- Department of Cancer Biology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA
| | - Weiqun Chen
- Department of Medical Laboratory, Central Hospital of Wuhan, Wuhan, China
| | - Chi Zhang
- Department of Medical Laboratory, Central Hospital of Wuhan, Wuhan, China
| | - Zhaoyang Zeng
- Department of Cancer Biology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA
- Key Laboratory of Carcinogenesis and Invasion, Ministry of Education, Xiangya Hospital; Cancer Research Institute, Xiangya School of Medicine, Central South University; Key Laboratory of Carcinogenesis, Chinese Ministry of Health, Changsha, China
| | - Ya Cao
- Key Laboratory of Carcinogenesis and Invasion, Ministry of Education, Xiangya Hospital; Cancer Research Institute, Xiangya School of Medicine, Central South University; Key Laboratory of Carcinogenesis, Chinese Ministry of Health, Changsha, China
| | - Zijun Y Xu-Monette
- Department of Pathology, Division of Hematopathology, Duke University Medical Center, Durham, NC, USA
| | - Ling Li
- Department of Oncology, the First Affiliated Hospital of Zhengzhou University; Lymphoma Diagnosis and Treatment Center of Henan Province, Zhengzhou, China
| | - Mingzhi Zhang
- Department of Oncology, the First Affiliated Hospital of Zhengzhou University; Lymphoma Diagnosis and Treatment Center of Henan Province, Zhengzhou, China
| | - Steven Rosenfeld
- Department of Cancer Biology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA
| | - Shideng Bao
- Department of Cancer Biology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA
| | - Eric Hsi
- Robert J. Tomsich Pathology and Laboratory Medicine Institute, Cleveland Clinic, Cleveland, OH, USA
| | - Ken H Young
- Department of Pathology, Division of Hematopathology, Duke University Medical Center, Durham, NC, USA
| | - Zhongxin Lu
- Department of Medical Laboratory, Central Hospital of Wuhan, Wuhan, China.
| | - Yong Li
- Department of Medicine, Section of Epidemiology and Population Sciences, Baylor College of Medicine, Houston, TX, USA.
- Department of Cancer Biology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA.
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16
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Kang C, LeRoith D, Gallagher EJ. Diabetes, Obesity, and Breast Cancer. Endocrinology 2018; 159:3801-3812. [PMID: 30215698 PMCID: PMC6202853 DOI: 10.1210/en.2018-00574] [Citation(s) in RCA: 141] [Impact Index Per Article: 20.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/13/2018] [Accepted: 09/05/2018] [Indexed: 12/13/2022]
Abstract
The rates of obesity and diabetes are increasing worldwide, whereas the age of onset for both obesity and diabetes are decreasing steadily. Obesity and diabetes are associated with multiple factors that contribute to the increased risk of a number of different cancers, including breast cancer. These factors are hyperinsulinemia, elevated IGFs, hyperglycemia, dyslipidemia, adipokines, inflammatory cytokines, and the gut microbiome. In this review, we discuss the current understanding of the complex signaling pathways underlying these multiple factors involved in the obesity/diabetes-breast cancer link, with a focus particularly on the roles of the insulin/IGF system and dyslipidemia in preclinical breast cancer models. We review some of the therapeutic strategies to target these metabolic derangements in cancer. Future research directions and potential therapeutic strategies are also discussed.
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Affiliation(s)
- Chifei Kang
- Division of Endocrinology, Diabetes and Bone Disease, Icahn School of Medicine at Mount Sinai, New York, New York
| | - Derek LeRoith
- Division of Endocrinology, Diabetes and Bone Disease, Icahn School of Medicine at Mount Sinai, New York, New York
| | - Emily J Gallagher
- Division of Endocrinology, Diabetes and Bone Disease, Icahn School of Medicine at Mount Sinai, New York, New York
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17
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Abstract
Early preclinical and population data suggested a role for the type I insulin-like growth factor receptor (IGF1R) in the regulation of breast cancer growth and survival. To target this pathway, multiple monoclonal antibodies and tyrosine kinase inhibitors were developed and tested in clinical trials. While some of the early clinical trials suggested a benefit for these drugs, none of the attempts showed improved outcomes when compared to conventional therapy. This failure of the IGF1R inhibitors was pronounced in breast cancer; multiple trials testing IGF1R inhibition in estrogen receptor-positive breast cancer were conducted, none showed benefit. This review will evaluate the rationale for IGF1R inhibition, discuss results of the clinical trials and suggest a path forward.
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Affiliation(s)
- Douglas Yee
- Masonic Cancer CenterUniversity of Minnesota, Minneapolis, Minnesota, USA
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18
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Boonyaratanakornkit V, Hamilton N, Márquez-Garbán DC, Pateetin P, McGowan EM, Pietras RJ. Extranuclear signaling by sex steroid receptors and clinical implications in breast cancer. Mol Cell Endocrinol 2018; 466:51-72. [PMID: 29146555 PMCID: PMC5878997 DOI: 10.1016/j.mce.2017.11.010] [Citation(s) in RCA: 31] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/10/2017] [Revised: 11/10/2017] [Accepted: 11/13/2017] [Indexed: 12/13/2022]
Abstract
Estrogen and progesterone play essential roles in the development and progression of breast cancer. Over 70% of breast cancers express estrogen receptors (ER) and progesterone receptors (PR), emphasizing the need for better understanding of ER and PR signaling. ER and PR are traditionally viewed as transcription factors that directly bind DNA to regulate gene networks. In addition to nuclear signaling, ER and PR mediate hormone-induced, rapid extranuclear signaling at the cell membrane or in the cytoplasm which triggers downstream signaling to regulate rapid or extended cellular responses. Specialized membrane and cytoplasmic proteins may also initiate hormone-induced extranuclear signaling. Rapid extranuclear signaling converges with its nuclear counterpart to amplify ER/PR transcription and specify gene regulatory networks. This review summarizes current understanding and updates on ER and PR extranuclear signaling. Further investigation of ER/PR extranuclear signaling may lead to development of novel targeted therapeutics for breast cancer management.
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Affiliation(s)
- Viroj Boonyaratanakornkit
- Department of Clinical Chemistry Faculty of Allied Health Sciences, Chulalongkorn University, Bangkok 10330, Thailand; Age-related Inflammation and Degeneration Research Unit, Chulalongkorn University, Bangkok 10330, Thailand; Graduate Program in Clinical Biochemistry and Molecular Medicine, Faculty of Allied Health Sciences, Chulalongkorn University, Bangkok 10330, Thailand.
| | - Nalo Hamilton
- UCLA Jonsson Comprehensive Cancer Center, Department of Medicine, Division of Hematology-Oncology, UCLA David Geffen School of Medicine, Los Angeles, CA 90095, USA
| | - Diana C Márquez-Garbán
- UCLA Jonsson Comprehensive Cancer Center, Department of Medicine, Division of Hematology-Oncology, UCLA David Geffen School of Medicine, Los Angeles, CA 90095, USA
| | - Prangwan Pateetin
- Graduate Program in Clinical Biochemistry and Molecular Medicine, Faculty of Allied Health Sciences, Chulalongkorn University, Bangkok 10330, Thailand
| | - Eileen M McGowan
- Chronic Disease Solutions Team, School of Life Sciences, University of Technology Sydney, Ultimo, 2007, Sydney, Australia
| | - Richard J Pietras
- UCLA Jonsson Comprehensive Cancer Center, Department of Medicine, Division of Hematology-Oncology, UCLA David Geffen School of Medicine, Los Angeles, CA 90095, USA
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19
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Arcidiacono D, Dedja A, Giacometti C, Fassan M, Nucci D, Francia S, Fabris F, Zaramella A, Gallagher EJ, Cassaro M, Rugge M, LeRoith D, Alberti A, Realdon S. Hyperinsulinemia Promotes Esophageal Cancer Development in a Surgically-Induced Duodeno-Esophageal Reflux Murine Model. Int J Mol Sci 2018; 19:1198. [PMID: 29662006 PMCID: PMC5979452 DOI: 10.3390/ijms19041198] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2018] [Revised: 04/08/2018] [Accepted: 04/11/2018] [Indexed: 01/10/2023] Open
Abstract
Hyperinsulinemia could have a role in the growing incidence of esophageal adenocarcinoma (EAC) and its pre-cancerous lesion, Barrett's Esophagus, a possible consequence of Gastro-Esophageal Reflux Disease. Obesity is known to mediate esophageal carcinogenesis through different mechanisms including insulin-resistance leading to hyperinsulinemia, which may mediate cancer progression via the insulin/insulin-like growth factor axis. We used the hyperinsulinemic non-obese FVB/N (Friend leukemia virus B strain) MKR (muscle (M)-IGF1R-lysine (K)-arginine (R) mouse model to evaluate the exclusive role of hyperinsulinemia in the pathogenesis of EAC related to duodeno-esophageal reflux. FVB/N wild-type (WT) and MKR mice underwent jejunum-esophageal anastomosis side-to end with the exclusion of the stomach. Thirty weeks after surgery, the esophagus was processed for histological, immunological and insulin/Insulin-like growth factor 1 (IGF1) signal transduction analyses. Most of the WT mice (63.1%) developed dysplasia, whereas most of the MKR mice (74.3%) developed squamous cell and adenosquamous carcinomas, both expressing Human Epidermal growth factor receptor 2 (HER2). Hyperinsulinemia significantly increased esophageal cancer incidence in the presence of duodenal-reflux. Insulin receptor (IR) and IGF1 receptor (IGF1R) were overexpressed in the hyperinsulinemic condition. IGF1R, through ERK1/2 mitogenic pattern activation, seems to be involved in cancer onset. Hyperinsulinemia-induced IGF1R and HER2 up-regulation could also increase the possibility of forming of IGF1R/HER2 heterodimers to support cell growth/proliferation/progression in esophageal carcinogenesis.
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Affiliation(s)
- Diletta Arcidiacono
- Digestive Endoscopy Unit, Veneto Institute of Oncology IOV-IRCCS, via Gattamelata, 64, 35128 Padua, Italy.
| | - Arben Dedja
- Department of Cardiac, Thoracic and Vascular Sciences, University of Padua, via Giustiniani 2, 35128 Padua, Italy.
| | - Cinzia Giacometti
- Anatomic Pathology Unit, ULSS 6 Euganea, via Cosma, 1, Camposampiero, 35012 Padua, Italy.
| | - Matteo Fassan
- Department of Medicine, Surgical Pathology & Cytopathology Unit, University of Padua, via Giustiniani 2, 35128 Padua, Italy.
| | - Daniele Nucci
- Digestive Endoscopy Unit, Veneto Institute of Oncology IOV-IRCCS, via Gattamelata, 64, 35128 Padua, Italy.
| | - Simona Francia
- Venetian Institute of Molecular Medicine-VIMM, via Orus, 2, 35129 Padua, Italy.
- Department of Biomedical Sciences, University of Padua, via Bassi, 58/B, 35131, Padua, Italy.
| | - Federico Fabris
- Venetian Institute of Molecular Medicine-VIMM, via Orus, 2, 35129 Padua, Italy.
- Department of Molecular Medicine, University of Padua, via Gabelli, 63, 35128 Padua, Italy.
| | - Alice Zaramella
- Venetian Institute of Molecular Medicine-VIMM, via Orus, 2, 35129 Padua, Italy.
- Department of Molecular Medicine, University of Padua, via Gabelli, 63, 35128 Padua, Italy.
| | - Emily J Gallagher
- Division of Endocrinology, Icahn School of Medicine at Mount Sinai, 1 Gustave L. Levy Pl, New York, NY 10029, USA.
| | - Mauro Cassaro
- Anatomic Pathology Unit, ULSS 6 Euganea, via Cosma, 1, Camposampiero, 35012 Padua, Italy.
| | - Massimo Rugge
- Department of Medicine, Surgical Pathology & Cytopathology Unit, University of Padua, via Giustiniani 2, 35128 Padua, Italy.
| | - Derek LeRoith
- Division of Endocrinology, Icahn School of Medicine at Mount Sinai, 1 Gustave L. Levy Pl, New York, NY 10029, USA.
| | - Alfredo Alberti
- Venetian Institute of Molecular Medicine-VIMM, via Orus, 2, 35129 Padua, Italy.
- Department of Molecular Medicine, University of Padua, via Gabelli, 63, 35128 Padua, Italy.
| | - Stefano Realdon
- Digestive Endoscopy Unit, Veneto Institute of Oncology IOV-IRCCS, via Gattamelata, 64, 35128 Padua, Italy.
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20
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Sundaram S, Yan L. Dietary energy restriction reduces high-fat diet-enhanced metastasis of Lewis lung carcinoma in mice. Oncotarget 2018; 7:65669-65675. [PMID: 27582541 PMCID: PMC5323183 DOI: 10.18632/oncotarget.11598] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2016] [Accepted: 08/11/2016] [Indexed: 01/29/2023] Open
Abstract
The objective of this study was to determine whether a reduction in energy intake ameliorated the high-fat diet-enhanced spontaneous metastasis of Lewis lung carcinoma in mice. Male C57BL/6 mice were fed the AIN93G diet, a high-fat diet or a high-fat diet with a 5% restriction of the intake. Energy restriction reduced body adiposity and body weight, but maintained growth similar to mice fed the AIN93G diet. The high-fat diet significantly increased the number and size (cross-sectional area and volume) of metastases formed in lungs. Restricted feeding reduced the number of metastases by 23%, metastatic cross-sectional area by 32% and volume by 45% compared to the high-fat diet. The high-fat diet elevated plasma concentrations of proinflammatory cytokines (monocyte chemotactic protein-1, plasminogen activator inhibitor-1, leptin), angiogenic factors (vascular endothelial growth factor, tissue inhibitor of metalloproteinase-1) and insulin. Restricted feeding significantly reduced the high-fat diet-induced elevations in plasma concentrations of proinflammatory cytokines, angiogenic factors and insulin. These results demonstrated that a reduction in diet intake by 5% reduced high-fat diet-enhanced metastasis, which may be associated with the mitigation of adiposity and down-regulation of cancer-promoting proinflammatory cytokines and angiogenic factors.
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Affiliation(s)
- Sneha Sundaram
- U.S. Department of Agriculture, Agricultural Research Service, Grand Forks Human Nutrition Research Center, Grand Forks, ND 58202, USA
| | - Lin Yan
- U.S. Department of Agriculture, Agricultural Research Service, Grand Forks Human Nutrition Research Center, Grand Forks, ND 58202, USA
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21
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Yan L, Sundaram S. Monocyte chemotactic protein-1 deficiency reduces spontaneous metastasis of Lewis lung carcinoma in mice fed a high-fat diet. Oncotarget 2017; 7:24792-9. [PMID: 27028862 PMCID: PMC5029742 DOI: 10.18632/oncotarget.8364] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2015] [Accepted: 02/28/2016] [Indexed: 01/28/2023] Open
Abstract
Adipose-produced pro-inflammatory cytokines contribute to obesity and cancer. This 2×2 experiment was designed to investigate effects of monocyte chemotactic protein-1 (MCP-1) deficiency on pulmonary metastasis of Lewis lung carcinoma (LLC) in MCP-1 deficient and wild-type mice fed a modified AIN93G diet containing 16% and 45% of energy from corn oil, respectively. The high-fat diet significantly increased the number and size (cross-sectional area and volume) of lung metastases compared to the AIN93G control diet. Deficiency in MCP-1 reduced lung metastases by 37% in high-fat diet-fed mice; it reduced metastatic cross-sectional area by 46% and volume by 69% compared to wild-type mice. Adipose and plasma concentrations of MCP-1 were significantly higher in high-fat diet-fed wild-type mice than in their AIN93G-fed counterparts; they were not detectable in MCP-1 deficient mice regardless of diet. Plasma concentrations of plasminogen activator inhibitor-1, tumor necrosis factor-α, vascular endothelial growth factor and tissue inhibitor of metalloproteinase-1 were significantly higher in MCP-1 deficient mice compared to wild-type mice. We conclude that adipose-produced MCP-1 contributes to high-fat diet-enhanced metastasis. While MCP-1 deficiency reduces metastasis, the elevation of pro-inflammatory cytokines and angiogenic factors in the absence of MCP-1 may support the metastatic development and growth of LLC in MCP-1 deficient mice.
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Affiliation(s)
- Lin Yan
- U.S. Department of Agriculture, Agricultural Research Service, Grand Forks Human Nutrition Research Center, Grand Forks, ND 58202, U.S.A
| | - Sneha Sundaram
- U.S. Department of Agriculture, Agricultural Research Service, Grand Forks Human Nutrition Research Center, Grand Forks, ND 58202, U.S.A
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22
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González N, Prieto I, del Puerto-Nevado L, Portal-Nuñez S, Ardura JA, Corton M, Fernández-Fernández B, Aguilera O, Gomez-Guerrero C, Mas S, Moreno JA, Ruiz-Ortega M, Sanz AB, Sanchez-Niño MD, Rojo F, Vivanco F, Esbrit P, Ayuso C, Alvarez-Llamas G, Egido J, García-Foncillas J, Ortiz A. 2017 update on the relationship between diabetes and colorectal cancer: epidemiology, potential molecular mechanisms and therapeutic implications. Oncotarget 2017; 8:18456-18485. [PMID: 28060743 PMCID: PMC5392343 DOI: 10.18632/oncotarget.14472] [Citation(s) in RCA: 125] [Impact Index Per Article: 15.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2016] [Accepted: 12/26/2016] [Indexed: 02/06/2023] Open
Abstract
Worldwide deaths from diabetes mellitus (DM) and colorectal cancer increased by 90% and 57%, respectively, over the past 20 years. The risk of colorectal cancer was estimated to be 27% higher in patients with type 2 DM than in non-diabetic controls. However, there are potential confounders, information from lower income countries is scarce, across the globe there is no correlation between DM prevalence and colorectal cancer incidence and the association has evolved over time, suggesting the impact of additional environmental factors. The clinical relevance of these associations depends on understanding the mechanism involved. Although evidence is limited, insulin use has been associated with increased and metformin with decreased incidence of colorectal cancer. In addition, colorectal cancer shares some cellular and molecular pathways with diabetes target organ damage, exemplified by diabetic kidney disease. These include epithelial cell injury, activation of inflammation and Wnt/β-catenin pathways and iron homeostasis defects, among others. Indeed, some drugs have undergone clinical trials for both cancer and diabetic kidney disease. Genome-wide association studies have identified diabetes-associated genes (e.g. TCF7L2) that may also contribute to colorectal cancer. We review the epidemiological evidence, potential pathophysiological mechanisms and therapeutic implications of the association between DM and colorectal cancer. Further studies should clarify the worldwide association between DM and colorectal cancer, strengthen the biological plausibility of a cause-and-effect relationship through characterization of the molecular pathways involved, search for specific molecular signatures of colorectal cancer under diabetic conditions, and eventually explore DM-specific strategies to prevent or treat colorectal cancer.
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Affiliation(s)
- Nieves González
- Renal, Vascular and Diabetes Research Laboratory, IIS-Fundacion Jimenez Diaz-UAM, Spanish Biomedical Research Network in Diabetes and Associated Metabolic Disorders (CIBERDEM), Madrid, Spain
| | - Isabel Prieto
- Radiation Oncology, Oncohealth Institute, IIS-Fundacion Jimenez Diaz-UAM, Madrid, Spain
| | - Laura del Puerto-Nevado
- Translational Oncology Division, Oncohealth Institute, IIS-Fundacion Jimenez Diaz-UAM, Madrid, Spain
| | - Sergio Portal-Nuñez
- Bone and Mineral Metabolism laboratory, IIS-Fundacion Jimenez Diaz-UAM, Madrid, Spain
| | - Juan Antonio Ardura
- Bone and Mineral Metabolism laboratory, IIS-Fundacion Jimenez Diaz-UAM, Madrid, Spain
| | - Marta Corton
- Genetics, IIS-Fundacion Jimenez Diaz-UAM, Madrid, Spain
| | | | - Oscar Aguilera
- Translational Oncology Division, Oncohealth Institute, IIS-Fundacion Jimenez Diaz-UAM, Madrid, Spain
| | | | - Sebastián Mas
- Nephrology, IIS-Fundacion Jimenez Diaz-UAM, Madrid, Spain
| | | | | | - Ana Belen Sanz
- Nephrology, IIS-Fundacion Jimenez Diaz-UAM, Madrid, Spain
- REDINREN, Madrid, Spain
| | | | - Federico Rojo
- Pathology, IIS-Fundacion Jimenez Diaz-UAM, Madrid, Spain
| | | | - Pedro Esbrit
- Bone and Mineral Metabolism laboratory, IIS-Fundacion Jimenez Diaz-UAM, Madrid, Spain
| | - Carmen Ayuso
- Genetics, IIS-Fundacion Jimenez Diaz-UAM, Madrid, Spain
| | | | - Jesús Egido
- Renal, Vascular and Diabetes Research Laboratory, IIS-Fundacion Jimenez Diaz-UAM, Spanish Biomedical Research Network in Diabetes and Associated Metabolic Disorders (CIBERDEM), Madrid, Spain
- Nephrology, IIS-Fundacion Jimenez Diaz-UAM, Madrid, Spain
| | - Jesús García-Foncillas
- Translational Oncology Division, Oncohealth Institute, IIS-Fundacion Jimenez Diaz-UAM, Madrid, Spain
| | - Alberto Ortiz
- Nephrology, IIS-Fundacion Jimenez Diaz-UAM, Madrid, Spain
- REDINREN, Madrid, Spain
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23
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Wu C, Liu Z, Zhang Z, Jiang Y, Zhang H. The effect of selected food phytochemicals on breast cancer metastasis based on in vivo capture of circulating tumor cells. Food Funct 2017; 8:2698-2701. [DOI: 10.1039/c7fo00420f] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/09/2023]
Abstract
The number of CTCs revealed dietary factor effects on cancer metastasis using a newin vivoCTC detection method.
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Affiliation(s)
- Chuanchen Wu
- College of Life Science
- Key Laboratory of Animal Resistance Biology of Shandong Province
- Key Laboratory of Food Nutrition and Safety
- Shandong Normal University
- Jinan
| | - Zhaochen Liu
- College of Life Science
- Key Laboratory of Animal Resistance Biology of Shandong Province
- Key Laboratory of Food Nutrition and Safety
- Shandong Normal University
- Jinan
| | - Zhen Zhang
- College of Life Science
- Key Laboratory of Animal Resistance Biology of Shandong Province
- Key Laboratory of Food Nutrition and Safety
- Shandong Normal University
- Jinan
| | - Yuehua Jiang
- Affiliated Hospital to Shandong University of Traditional Chinese Medicine
- Jinan
- PR China
| | - Hongyan Zhang
- College of Life Science
- Key Laboratory of Animal Resistance Biology of Shandong Province
- Key Laboratory of Food Nutrition and Safety
- Shandong Normal University
- Jinan
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24
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Levin ER, Hammes SR. Nuclear receptors outside the nucleus: extranuclear signalling by steroid receptors. Nat Rev Mol Cell Biol 2016; 17:783-797. [PMID: 27729652 PMCID: PMC5649368 DOI: 10.1038/nrm.2016.122] [Citation(s) in RCA: 200] [Impact Index Per Article: 22.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
Steroid hormone receptors mediate numerous crucial biological processes and are classically thought to function as transcriptional regulators in the nucleus. However, it has been known for more than 50 years that steroids evoke rapid responses in many organs that cannot be explained by gene regulation. Mounting evidence indicates that most steroid receptors in fact exist in extranuclear cellular pools, including at the plasma membrane. This latter pool, when engaged by a steroid ligand, rapidly activates signals that affect various aspects of cellular biology. Research into the mechanisms of signalling instigated by extranuclear steroid receptor pools and how this extranuclear signalling is integrated with responses elicited by nuclear receptor pools provides novel understanding of steroid hormone signalling and its roles in health and disease.
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Affiliation(s)
- Ellis R. Levin
- Department of Medicine and Biochemistry, University of California,
Irvine and the Long Beach VA Medical Center, California 90822, USA
| | - Stephen R. Hammes
- Departments of Medicine and Pharmacology, University of Rochester,
Rochester, New York 14642, USA
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25
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Zelenko Z, Gallagher EJ, Antoniou IM, Sachdev D, Nayak A, Yee D, LeRoith D. EMT reversal in human cancer cells after IR knockdown in hyperinsulinemic mice. Endocr Relat Cancer 2016; 23:747-58. [PMID: 27435064 PMCID: PMC4990486 DOI: 10.1530/erc-16-0142] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/02/2016] [Accepted: 07/19/2016] [Indexed: 12/26/2022]
Abstract
Type 2 diabetes (T2D) is associated with increased cancer risk and cancer-related mortality. Data herein show that we generated an immunodeficient hyperinsulinemic mouse by crossing the Rag1(-/-) mice, which have no mature B or T lymphocytes, with the MKR mouse model of T2D to generate the Rag1(-/-) (Rag/WT) and Rag1(-/-)/MKR(+/+) (Rag/MKR) mice. The female Rag/MKR mice are insulin resistant and have significantly higher nonfasting plasma insulin levels compared with the Rag/WT controls. Therefore, we used these Rag/MKR mice to investigate the role of endogenous hyperinsulinemia on human cancer progression. In this study, we show that hyperinsulinemia in the Rag/MKR mice increases the expression of mesenchymal transcription factors, TWIST1 and ZEB1, and increases the expression of the angiogenesis marker, vascular endothelial growth factor A (VEGFA). We also show that silencing the insulin receptor (IR) in the human LCC6 cancer cells leads to decreased tumor growth and metastases, suppression of mesenchymal markers vimentin, SLUG, TWIST1 and ZEB1, suppression of angiogenesis markers, VEGFA and VEGFD, and re-expression of the epithelial marker, E-cadherin. The data in this paper demonstrate that IR knockdown in primary tumors partially reverses the growth-promoting effects of hyperinsulinemia as well as highlighting the importance of the insulin receptor signaling pathway in cancer progression, and more specifically in epithelial-mesenchymal transition.
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MESH Headings
- Animals
- Cell Line, Tumor
- Diabetes Mellitus, Type 2/genetics
- Diabetes Mellitus, Type 2/pathology
- Disease Models, Animal
- Epithelial-Mesenchymal Transition
- Female
- Gene Silencing
- Humans
- Hyperinsulinism/genetics
- Hyperinsulinism/metabolism
- Hyperinsulinism/pathology
- Male
- Mammary Neoplasms, Experimental/genetics
- Mammary Neoplasms, Experimental/metabolism
- Mammary Neoplasms, Experimental/pathology
- Mice, Transgenic
- Nuclear Proteins/genetics
- Nuclear Proteins/metabolism
- Receptor, Insulin/genetics
- Receptor, Insulin/metabolism
- Signal Transduction
- Snail Family Transcription Factors/genetics
- Snail Family Transcription Factors/metabolism
- Twist-Related Protein 1/genetics
- Twist-Related Protein 1/metabolism
- Vascular Endothelial Growth Factor A
- Vimentin/metabolism
- Zinc Finger E-box-Binding Homeobox 1/genetics
- Zinc Finger E-box-Binding Homeobox 1/metabolism
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Affiliation(s)
- Zara Zelenko
- Division of EndocrinologyDiabetes and Bone Diseases, Icahn School of Medicine at Mount Sinai, New York, New York, USA
| | - Emily Jane Gallagher
- Division of EndocrinologyDiabetes and Bone Diseases, Icahn School of Medicine at Mount Sinai, New York, New York, USA
| | - Irini Markella Antoniou
- Division of EndocrinologyDiabetes and Bone Diseases, Icahn School of Medicine at Mount Sinai, New York, New York, USA
| | - Deepali Sachdev
- Department of Medicine and Masonic Cancer CenterUniversity of Minnesota, Minneapolis, Minnesota, USA
| | - Anupma Nayak
- Department of Pathology and Laboratory MedicineThe Mount Sinai Hospital and Icahn School of Medicine at Mount Sinai, New York, New York, USA
| | - Douglas Yee
- Department of Medicine and Masonic Cancer CenterUniversity of Minnesota, Minneapolis, Minnesota, USA
| | - Derek LeRoith
- Division of EndocrinologyDiabetes and Bone Diseases, Icahn School of Medicine at Mount Sinai, New York, New York, USA
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26
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Gallagher EJ, Zelenko Z, Tobin-Hess A, Werner U, Tennagels N, LeRoith D. Non-metabolisable insulin glargine does not promote breast cancer growth in a mouse model of type 2 diabetes. Diabetologia 2016; 59:2018-25. [PMID: 27241182 PMCID: PMC4970885 DOI: 10.1007/s00125-016-4000-x] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/15/2016] [Accepted: 05/03/2016] [Indexed: 12/29/2022]
Abstract
AIMS/HYPOTHESIS Previous epidemiological studies have reported a potential link between insulin analogues and breast cancer; however, a prospective randomised controlled trial showed neutral effects of insulin glargine on cancer risk. Insulin glargine is metabolised in vivo to an M1 metabolite. A question remains whether a subset of individuals with slower rates of glargine metabolism or who are on high doses could, theoretically, have an increased risk of cancer progression if a tumour is already present. In this study, we aimed to determine whether a non-metabolisable form of insulin glargine induced murine breast cancer growth. METHODS A mouse model of type 2 diabetes (MKR) was used for these studies. MKR mice were injected with two murine mammary cancer cell lines: Mvt-1 cells (derived from MMTV-c-Myc/Vegf tumours) and Met1 cells (derived from MMTV-polyoma virus middle T antigen tumours). Mice were treated with 25 U/kg per day of the long-acting insulin analogues, insulin glargine, insulin detemir, insulin degludec or non-metabolisable glargine, or vehicle. RESULTS No difference in tumour growth was seen in terms of tumour size after insulin glargine, detemir, degludec or vehicle injections. Non-metabolisable glargine did not increase tumour growth compared with insulin glargine or vehicle. Insulin glargine and non-metabolisable glargine led to insulin receptor phosphorylation in vivo rather than IGF-1 receptor phosphorylation. CONCLUSIONS/INTERPRETATION These results demonstrate that in a mouse model of type 2 diabetes, at high concentrations, basal insulin analogues and a non-metabolisable glargine analogue do not promote the progression of breast tumours.
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Affiliation(s)
- Emily J Gallagher
- Division of Endocrinology, Diabetes and Bone Diseases, Department of Medicine, Icahn School of Medicine at Mount Sinai, One Gustave L Levy Place, Box 1055, New York, NY, 10029, USA.
| | - Zara Zelenko
- Division of Endocrinology, Diabetes and Bone Diseases, Department of Medicine, Icahn School of Medicine at Mount Sinai, One Gustave L Levy Place, Box 1055, New York, NY, 10029, USA
| | - Aviva Tobin-Hess
- Division of Endocrinology, Diabetes and Bone Diseases, Department of Medicine, Icahn School of Medicine at Mount Sinai, One Gustave L Levy Place, Box 1055, New York, NY, 10029, USA
| | - Ulrich Werner
- Diabetes Research & Translational Medicine, Insulin Biology, Sanofi-Aventis Deutschland GmbH, Frankfurt am Main, Germany
| | - Norbert Tennagels
- Diabetes Research & Translational Medicine, Insulin Biology, Sanofi-Aventis Deutschland GmbH, Frankfurt am Main, Germany
| | - Derek LeRoith
- Division of Endocrinology, Diabetes and Bone Diseases, Department of Medicine, Icahn School of Medicine at Mount Sinai, One Gustave L Levy Place, Box 1055, New York, NY, 10029, USA
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27
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Zelenko Z, Gallagher EJ, Tobin-Hess A, Belardi V, Rostoker R, Blank J, Dina Y, LeRoith D. Silencing vimentin expression decreases pulmonary metastases in a pre-diabetic mouse model of mammary tumor progression. Oncogene 2016; 36:1394-1403. [PMID: 27568979 PMCID: PMC5332535 DOI: 10.1038/onc.2016.305] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2015] [Revised: 06/25/2016] [Accepted: 07/22/2016] [Indexed: 01/27/2023]
Abstract
Increased breast cancer risk and mortality has been associated with obesity and Type 2 diabetes (T2D). Hyperinsulinemia, a key factor in obesity, pre-diabetes and T2D, has been associated with decreased breast cancer survival. In the current study, a mouse model of pre-diabetes (MKR mouse) was used to investigate the mechanisms through which endogenous hyperinsulinemia promotes mammary tumor metastases. The MKR mice developed larger primary tumors and greater number of pulmonary metastases compared to wild type (WT) mice after injection with c-Myc/Vegf overexpressing MVT-1 cells. Analysis of the primary tumors showed significant increase in Vimentin protein expression in the MKR mice compared to WT. We hypothesized that Vimentin was an important mediator in the effect of hyperinsulinemia on breast cancer metastasis. Lentiviral shRNA knockdown of Vimentin led to a significant decrease in invasion of the MVT-1 cells and abrogated the increase in cell invasion in response to insulin. In the pre-diabetic MKR mouse, Vimentin knockdown led to a decrease in pulmonary metastases. In vitro, we found that insulin increased pAKT, prevented Caspase 3 activation, and increased Vimentin. Inhibiting the PI3K/AKT pathway, using NVP-BKM120, increased active Caspase 3 and decreased Vimentin levels. This study is the first to show that Vimentin plays an important role in tumor metastasis in vivo in the setting of pre-diabetes and endogenous hyperinsulinemia. Vimentin targeting may be an important therapeutic strategy to reduce metastases in patients with obesity, pre-diabetes or T2D.
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Affiliation(s)
- Z Zelenko
- Division of Endocrinology, Diabetes and Bone Diseases, Icahn School of Medicine at Mount Sinai, New York City, NY, USA
| | - E J Gallagher
- Division of Endocrinology, Diabetes and Bone Diseases, Icahn School of Medicine at Mount Sinai, New York City, NY, USA
| | - A Tobin-Hess
- Division of Endocrinology, Diabetes and Bone Diseases, Icahn School of Medicine at Mount Sinai, New York City, NY, USA
| | - V Belardi
- Division of Endocrinology, Diabetes and Bone Diseases, Icahn School of Medicine at Mount Sinai, New York City, NY, USA
| | - R Rostoker
- Clinical Research Institute at Rambam (CRIR) and the Faculty of Medicine, Technion, Diabetes and Metabolism Clinical Research Center of Excellence, Haifa, Israel
| | - J Blank
- Division of Endocrinology, Diabetes and Bone Diseases, Icahn School of Medicine at Mount Sinai, New York City, NY, USA
| | - Y Dina
- Division of Endocrinology, Diabetes and Bone Diseases, Icahn School of Medicine at Mount Sinai, New York City, NY, USA
| | - D LeRoith
- Division of Endocrinology, Diabetes and Bone Diseases, Icahn School of Medicine at Mount Sinai, New York City, NY, USA.,Clinical Research Institute at Rambam (CRIR) and the Faculty of Medicine, Technion, Diabetes and Metabolism Clinical Research Center of Excellence, Haifa, Israel
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28
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Shin M, Yang EG, Song HK, Jeon H. Insulin activates EGFR by stimulating its interaction with IGF-1R in low-EGFR-expressing TNBC cells. BMB Rep 2016; 48:342-7. [PMID: 25341922 PMCID: PMC4578621 DOI: 10.5483/bmbrep.2015.48.6.157] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2014] [Indexed: 01/11/2023] Open
Abstract
The expression of epidermal growth factor receptor (EGFR) is an important diagnostic marker for triple-negative breast cancer (TNBC) cells, which lack three hormonal receptors: estrogen and progesterone receptors as well as epidermal growth factor receptor 2. EGFR transactivation can cause drug resistance in many cancers including TNBC, but the mechanism underlying this phenomenon is poorly defined. Here, we demonstrate that insulin treatment induces EGFR activation by stimulating the interaction of EGFR with insulin-like growth factor receptor 1 (IGF-1R) in the MDA-MB-436 TNBC cell line. These cells express low levels of EGFR, while exhibiting high levels of IGF-1R expression and phosphorylation. Low-EGFRexpressing MDA-MB-436 cells show high sensitivity to insulinstimulated cell growth. Therefore, unexpectedly, insulin stimulation induced EGFR transactivation by regulating its interaction with IGF-1R in low-EGFR-expressing TNBC cells.
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Affiliation(s)
- Miyoung Shin
- Division of Life Sciences, Korea University, Seoul 136-701; Center for Theragnosis, Biomedical Research Institute, Korea Institute of Science and Technology, Seoul 136-791, Korea
| | - Eun Gyeong Yang
- Center for Theragnosis, Biomedical Research Institute, Korea Institute of Science and Technology, Seoul 136-791, Korea
| | - Hyun Kyu Song
- Division of Life Sciences, Korea University, Seoul 136-701, Korea
| | - Hyesung Jeon
- Center for Theragnosis, Biomedical Research Institute, Korea Institute of Science and Technology, Seoul 136-791, Korea; Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA
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29
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Monzavi-Karbassi B, Gentry R, Kaur V, Siegel ER, Jousheghany F, Medarametla S, Fuhrman BJ, Safar AM, Hutchins LF, Kieber-Emmons T. Pre-diagnosis blood glucose and prognosis in women with breast cancer. Cancer Metab 2016; 4:7. [PMID: 27054036 PMCID: PMC4822279 DOI: 10.1186/s40170-016-0147-7] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2015] [Accepted: 03/16/2016] [Indexed: 12/02/2022] Open
Abstract
Background The effect of moderately elevated blood glucose levels among non-diabetic subjects on cancer prognosis is not well described. The goal of this study was to examine the association of elevated random blood glucose (RBG) levels in non-diabetic breast cancer patients with overall survival (OS) and time to tumor recurrence (TTR). Results Forty-nine deaths and 32 recurrences occurred among 148 eligible study subjects during 855.44 person-years of follow-up, with median follow-up of 5.97 years. We observed that patients with elevated RBG levels experienced significantly shorter OS (hazard ratio [HR], 3.01; 95 % confidence interval [CI] (1.70–5.33); P < 0.001) and shorter TTR (HR, 2.08; CI (1.04–4.16); P = 0.04) as compared to patients with non-elevated RBG levels. After controlling for tumor grade, tumor stage, race, and BMI, elevated RBG continued to display high and statistically significant association with shorter OS (HR, 3.50; CI (1.87–6.54); P < 0.001). Adjustment for age, race, and BMI strengthened HR of RBG for TTR. The association of RGB with TTR lost its borderline statistical significance upon controlling for both tumor grade and stage. Conclusions The data suggest that elevated blood glucose is associated with poor prognosis of breast cancer patients. Given the potential clinical implication, these findings warrant further investigation.
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Affiliation(s)
- Behjatolah Monzavi-Karbassi
- Winthrop P. Rockefeller Cancer Institute, University of Arkansas for Medical Sciences, Little Rock, AR 72205 USA ; Department of Pathology, University of Arkansas for Medical Sciences, 4301 West Markham St., Slot #824, Little Rock, AR 72205 USA
| | - Rhonda Gentry
- Winthrop P. Rockefeller Cancer Institute, University of Arkansas for Medical Sciences, Little Rock, AR 72205 USA ; Division of Hematology/Oncology, University of Arkansas for Medical Sciences, Little Rock, AR 72205 USA
| | - Varinder Kaur
- Winthrop P. Rockefeller Cancer Institute, University of Arkansas for Medical Sciences, Little Rock, AR 72205 USA ; Division of Hematology/Oncology, University of Arkansas for Medical Sciences, Little Rock, AR 72205 USA
| | - Eric R Siegel
- Winthrop P. Rockefeller Cancer Institute, University of Arkansas for Medical Sciences, Little Rock, AR 72205 USA ; Department of Biostatistics, University of Arkansas for Medical Sciences, Little Rock, AR 72205 USA
| | - Fariba Jousheghany
- Winthrop P. Rockefeller Cancer Institute, University of Arkansas for Medical Sciences, Little Rock, AR 72205 USA
| | - Srikanth Medarametla
- Winthrop P. Rockefeller Cancer Institute, University of Arkansas for Medical Sciences, Little Rock, AR 72205 USA
| | - Barbara J Fuhrman
- Department of Epidemiology, University of Arkansas for Medical Sciences, Little Rock, AR 72205 USA
| | - A Mazin Safar
- Winthrop P. Rockefeller Cancer Institute, University of Arkansas for Medical Sciences, Little Rock, AR 72205 USA ; Division of Hematology/Oncology, University of Arkansas for Medical Sciences, Little Rock, AR 72205 USA
| | - Laura F Hutchins
- Winthrop P. Rockefeller Cancer Institute, University of Arkansas for Medical Sciences, Little Rock, AR 72205 USA ; Division of Hematology/Oncology, University of Arkansas for Medical Sciences, Little Rock, AR 72205 USA
| | - Thomas Kieber-Emmons
- Winthrop P. Rockefeller Cancer Institute, University of Arkansas for Medical Sciences, Little Rock, AR 72205 USA ; Department of Pathology, University of Arkansas for Medical Sciences, 4301 West Markham St., Slot #824, Little Rock, AR 72205 USA
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30
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Diabetes and cancer, common threads and missing links. Cancer Lett 2016; 374:54-61. [PMID: 26879686 DOI: 10.1016/j.canlet.2016.02.006] [Citation(s) in RCA: 47] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2015] [Revised: 02/03/2016] [Accepted: 02/03/2016] [Indexed: 02/07/2023]
Abstract
Diabetes mellitus is a serious and growing health problem worldwide and is associated with severe acute and chronic complications. Accruing epidemiological and clinical evidence have suggested that an increased cancer incidence is associated with diabetes as well as certain diabetes risk factors and diabetes medications. Several pathophysiological mechanisms for this relationship have been postulated, including insulin resistance and hyperinsulinemia, enhanced inflammation, aberrant metabolic state, endoplasmic reticulum stress, and deregulation of autophagy. In addition to these potential mechanisms, a number of common risk factors, including obesity, may be behind the association between diabetes and cancer. Furthermore, different anti-diabetic medications may modify cancer risk and mortality in patients with diabetes. This Review discusses evidence to support the relationship between diabetes and cancer development as well as the underlying mechanisms. We also discuss the relationship of current diabetes treatments and cancer risk or prognosis. Understanding the mechanisms that connect type 2 diabetes or diabetes treatments to cancer are crucial for establishing the fundamental strategies concerning about primary prevention, early detection and effective therapy against these diseases.
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31
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Ben-Shmuel S, Rostoker R, Scheinman EJ, LeRoith D. Metabolic Syndrome, Type 2 Diabetes, and Cancer: Epidemiology and Potential Mechanisms. Handb Exp Pharmacol 2016; 233:355-372. [PMID: 25903410 DOI: 10.1007/164_2015_12] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/04/2023]
Abstract
Obesity is associated with multiple metabolic disorders that drive cardiovascular disease, T2D and cancer. The doubling in the number of obese adults over the past 3 decades led to the recognition of obesity as a "disease". With over 42 million children obese or overweight, this epidemic is rapidly growing worldwide. Obesity and T2D are both associated together and independently with an increased risk for cancer and a worse prognosis. Accumulating evidence from epidemiological studies revealed potential factors that may explain the association between obesity-linked metabolic disorders and cancer risk. Studies based on the insulin resistance MKR mice, highlighted the roe of the insulin receptor and its downstream signaling proteins in mediating hyperinsulinemia's mitogenic effects. Hypercholesterolemia was also shown to promote the formation of larger tumors and enhancement in metastasis. Furthermore, the conversion of cholesterol into 27-Hydroxycholesterol was found to link high fat diet-induced hypercholesterolemia with cancer pathophysiology. Alteration in circulating adipokines and cytokines are commonly found in obesity and T2D. Adipokines are involved in tumor growth through multiple mechanisms including mTOR, VEGF and cyclins. In addition, adipose tissues are known to recruit and alter macrophage phenotype; these macrophages can promote cancer progression by secreting inflammatory cytokines such as TNF-α and IL-6. Better characterization on the above factors and their downstream effects is required in order to translate the current knowledge into the clinic, but more importantly is to understand which are the key factors that drive cancer in each patient. Until we reach this point, policies and activities toward healthy diets and physical activities remain the best medicine.
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Affiliation(s)
- Sarit Ben-Shmuel
- Clinical Research Institute at Rambam (CRIR), Diabetes and Metabolism Clinical Research Center of Excellence, Rambam Health Care Campus, Haifa, Israel
| | - Ran Rostoker
- Clinical Research Institute at Rambam (CRIR), Diabetes and Metabolism Clinical Research Center of Excellence, Rambam Health Care Campus, Haifa, Israel
| | - Eyal J Scheinman
- Clinical Research Institute at Rambam (CRIR), Diabetes and Metabolism Clinical Research Center of Excellence, Rambam Health Care Campus, Haifa, Israel
| | - Derek LeRoith
- Clinical Research Institute at Rambam (CRIR), Diabetes and Metabolism Clinical Research Center of Excellence, Rambam Health Care Campus, Haifa, Israel.
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32
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Gallagher EJ, LeRoith D. Obesity and Diabetes: The Increased Risk of Cancer and Cancer-Related Mortality. Physiol Rev 2015; 95:727-48. [PMID: 26084689 DOI: 10.1152/physrev.00030.2014] [Citation(s) in RCA: 526] [Impact Index Per Article: 52.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023] Open
Abstract
Obesity and type 2 diabetes are becoming increasingly prevalent worldwide, and both are associated with an increased incidence and mortality from many cancers. The metabolic abnormalities associated with type 2 diabetes develop many years before the onset of diabetes and, therefore, may be contributing to cancer risk before individuals are aware that they are at risk. Multiple factors potentially contribute to the progression of cancer in obesity and type 2 diabetes, including hyperinsulinemia and insulin-like growth factor I, hyperglycemia, dyslipidemia, adipokines and cytokines, and the gut microbiome. These metabolic changes may contribute directly or indirectly to cancer progression. Intentional weight loss may protect against cancer development, and therapies for diabetes may prove to be effective adjuvant agents in reducing cancer progression. In this review we discuss the current epidemiology, basic science, and clinical data that link obesity, diabetes, and cancer and how treating obesity and type 2 diabetes could also reduce cancer risk and improve outcomes.
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Affiliation(s)
| | - Derek LeRoith
- Icahn School of Medicine at Mount Sinai, New York, New York
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33
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Insulin Effects on Survival of Human Multiple Myeloma Cells. Bull Exp Biol Med 2015; 159:262-5. [PMID: 26087753 DOI: 10.1007/s10517-015-2937-2] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2013] [Indexed: 10/23/2022]
Abstract
Insulin effects of human multiple myeloma cell survival were studied on RPMI1640, RPMI8226, and IM9 lines differing by differentiation degree. The effects of exogenous insulin on tumor cell growth and survival varied. Insulin alone did not improve the viability of myeloma cells, while in combination with serum growth factors increased it. The IM9 cells with immunophenotype (CD(138+), CD(38-), CD(45+), CD(56-), CD(19+)) exhibited the highest sensitivity to serum growth factors, while RPMI1640 and RPMI8226 cells with (CD(138+), CD(38+), CD(45-), CD(56±), CD(19-)) immunophenotype were less sensitive. Studies of gene expression showed a significantly lower level of IRA mRNA expression in IM9 vs. RPMI1640 and RPMI8226 cells.
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34
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Rostoker R, Abelson S, Genkin I, Ben-Shmuel S, Sachidanandam R, Scheinman EJ, Bitton-Worms K, Orr ZS, Caspi A, Tzukerman M, LeRoith D. CD24(+) cells fuel rapid tumor growth and display high metastatic capacity. Breast Cancer Res 2015; 17:78. [PMID: 26040280 PMCID: PMC4479226 DOI: 10.1186/s13058-015-0589-9] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2015] [Accepted: 05/18/2015] [Indexed: 12/19/2022] Open
Abstract
Introduction Breast tumors are comprised of distinct cancer cell populations which differ in their tumorigenic and metastatic capacity. Characterization of cell surface markers enables investigators to distinguish between cancer stem cells and their counterparts. CD24 is a well-known cell surface marker for mammary epithelial cells isolation, recently it was suggested as a potential prognostic marker in a wide variety of malignancies. Here, we demonstrate that CD24+ cells create intra-tumor heterogeneity, and display highly metastatic properties. Methods The mammary carcinoma Mvt1 cells were sorted into CD24− and CD24+ cells. Both subsets were morphologically and phenotypically characterized, and tumorigenic capacity was assessed via orthotopic inoculation of each subset into the mammary fat pad of wild-type and MKR mice. The metastatic capacity of each subset was determined with the tail vein metastasis assay. The role of CD24 in tumorigenesis was further examined with shRNA technology. GFP-labeled cells were monitored in vivo for differentiation. The genetic profile of each subset was analyzed using RNA sequencing. Results CD24+ cells displayed a more spindle-like cytoplasm. The cells formed mammospheres in high efficiency and CD24+ tumors displayed rapid growth in both WT and MKR mice, and were more metastatic than CD24- cells. Interestingly, CD24-KD in CD24+ cells had no effect both in vitro and in vivo on the various parameters studied. Moreover, CD24+ cells gave rise in vivo to the CD24− that comprised the bulk of the tumor. RNA-seq analysis revealed enrichment of genes and pathways of the extracellular matrix in the CD24+ cells. Conclusion CD24+ cells account for heterogeneity in mammary tumors. CD24 expression at early stages of the cancer process is an indication of a highly invasive tumor. However, CD24 is not a suitable therapeutic target; instead we suggest here new potential targets accounting for early differentiated cancer cells tumorigenic capacity. Electronic supplementary material The online version of this article (doi:10.1186/s13058-015-0589-9) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Ran Rostoker
- Diabetes and Metabolism Clinical Research Center of Excellence, Clinical Research Institute at Rambam (CRIR) and the Faculty of Medicine, Technion, Rambam Medical Center, P.O.B 9602, Haifa, 31096, Israel.
| | - Sagi Abelson
- Laboratory of Molecular Medicine, Rambam Health Care Campus and Rappaport Faculty of Medicine and Research Institute, Technion, Haifa, 31096, Israel.
| | - Inna Genkin
- Diabetes and Metabolism Clinical Research Center of Excellence, Clinical Research Institute at Rambam (CRIR) and the Faculty of Medicine, Technion, Rambam Medical Center, P.O.B 9602, Haifa, 31096, Israel.
| | - Sarit Ben-Shmuel
- Diabetes and Metabolism Clinical Research Center of Excellence, Clinical Research Institute at Rambam (CRIR) and the Faculty of Medicine, Technion, Rambam Medical Center, P.O.B 9602, Haifa, 31096, Israel.
| | - Ravi Sachidanandam
- Department of Oncological Science, Icahn School of Medicine at Mt Sinai and the James J Peters VA Medical Center, New York, USA.
| | - Eyal J Scheinman
- Diabetes and Metabolism Clinical Research Center of Excellence, Clinical Research Institute at Rambam (CRIR) and the Faculty of Medicine, Technion, Rambam Medical Center, P.O.B 9602, Haifa, 31096, Israel.
| | - Keren Bitton-Worms
- Diabetes and Metabolism Clinical Research Center of Excellence, Clinical Research Institute at Rambam (CRIR) and the Faculty of Medicine, Technion, Rambam Medical Center, P.O.B 9602, Haifa, 31096, Israel.
| | - Zila Shen Orr
- Diabetes and Metabolism Clinical Research Center of Excellence, Clinical Research Institute at Rambam (CRIR) and the Faculty of Medicine, Technion, Rambam Medical Center, P.O.B 9602, Haifa, 31096, Israel.
| | - Avishay Caspi
- Diabetes and Metabolism Clinical Research Center of Excellence, Clinical Research Institute at Rambam (CRIR) and the Faculty of Medicine, Technion, Rambam Medical Center, P.O.B 9602, Haifa, 31096, Israel.
| | - Maty Tzukerman
- Laboratory of Molecular Medicine, Rambam Health Care Campus and Rappaport Faculty of Medicine and Research Institute, Technion, Haifa, 31096, Israel.
| | - Derek LeRoith
- Diabetes and Metabolism Clinical Research Center of Excellence, Clinical Research Institute at Rambam (CRIR) and the Faculty of Medicine, Technion, Rambam Medical Center, P.O.B 9602, Haifa, 31096, Israel. .,Division of Endocrinology, Diabetes and Bone Disease, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
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Rutkowski MR, Svoronos N, Perales-Puchalt A, Conejo-Garcia JR. The Tumor Macroenvironment: Cancer-Promoting Networks Beyond Tumor Beds. Adv Cancer Res 2015. [PMID: 26216635 DOI: 10.1016/bs.acr.2015.04.011] [Citation(s) in RCA: 47] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
During tumor progression, alterations within the systemic tumor environment, or macroenvironment, result in the promotion of tumor growth, tumor invasion to distal organs, and eventual metastatic disease. Distally produced hormones, commensal microbiota residing within mucosal surfaces, myeloid cells and even the bone marrow impact the systemic immune system, tumor growth, and metastatic spread. Understanding the reciprocal interactions between the cells and soluble factors within the macroenvironment and the primary tumor will enable the design of specific therapies that have the potential to prevent dissemination and metastatic spread. This chapter will summarize recent findings detailing how the primary tumor and systemic tumor macroenvironment coordinate malignant progression.
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Affiliation(s)
- Melanie R Rutkowski
- Tumor Microenvironment and Metastasis Program, The Wistar Institute, Philadelphia, Pennsylvania, USA
| | - Nikolaos Svoronos
- Tumor Microenvironment and Metastasis Program, The Wistar Institute, Philadelphia, Pennsylvania, USA
| | - Alfredo Perales-Puchalt
- Tumor Microenvironment and Metastasis Program, The Wistar Institute, Philadelphia, Pennsylvania, USA
| | - Jose R Conejo-Garcia
- Tumor Microenvironment and Metastasis Program, The Wistar Institute, Philadelphia, Pennsylvania, USA.
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Kumar A, Shiloach J, Betenbaugh MJ, Gallagher EJ. The beta-3 adrenergic agonist (CL-316,243) restores the expression of down-regulated fatty acid oxidation genes in type 2 diabetic mice. Nutr Metab (Lond) 2015; 12:8. [PMID: 25784953 PMCID: PMC4362840 DOI: 10.1186/s12986-015-0003-8] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2014] [Accepted: 02/05/2015] [Indexed: 02/07/2023] Open
Abstract
Background The hallmark of Type 2 diabetes (T2D) is hyperglycemia, although there are multiple other metabolic abnormalities that occur with T2D, including insulin resistance and dyslipidemia. To advance T2D prevention and develop targeted therapies for its treatment, a greater understanding of the alterations in metabolic tissues associated with T2D is necessary. The aim of this study was to use microarray analysis of gene expression in metabolic tissues from a mouse model of pre-diabetes and T2D to further understand the metabolic abnormalities that may contribute to T2D. We also aimed to uncover the novel genes and pathways regulated by the insulin sensitizing agent (CL-316,243) to identify key pathways and target genes in metabolic tissues that can reverse the diabetic phenotype. Methods Male MKR mice on an FVB/n background and age matched wild-type (WT) FVB/n mice were used in all experiments. Skeletal muscle, liver and fat were isolated from prediabetic (3 week old) and diabetic (8 week old) MKR mice. Male MKR mice were treated with CL-316,243. Skeletal muscle, liver and fat were isolated after the treatment period. RNA was isolated from the metabolic tissues and subjected to microarray and KEGG database analysis. Results Significant decreases in the expression of mitochondrial and peroxisomal fatty acid oxidation genes were found in the skeletal muscle and adipose tissue of adult MKR mice, and the liver of pre-diabetic MKR mice, compared to WT controls. After treatment with CL-316,243, the circulating glucose and insulin concentrations in the MKR mice improved, an increase in the expression of peroxisomal fatty acid oxidation genes was observed in addition to a decrease in the expression of retinaldehyde dehydrogenases. These genes were not previously known to be regulated by CL-316,243 treatment. Conclusions This study uncovers novel genes that may contribute to pharmacological reversal of insulin resistance and T2D and may be targets for treatment. In addition, it explains the lower free fatty acid levels in MKR mice after treatment with CL-316,243 and furthermore, it provides biomarker genes such as ACAA1 and HSD17b4 which could be further probed in a future study. Electronic supplementary material The online version of this article (doi:10.1186/s12986-015-0003-8) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Amit Kumar
- Biotechnology Core Laboratory, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bldg 14A, Bethesda, MD 20892 USA ; Department of Chemical & Biomolecular Engineering, Johns Hopkins University, 3400 North Charles Street, Baltimore, MD 21218-2686 USA
| | - Joseph Shiloach
- Biotechnology Core Laboratory, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bldg 14A, Bethesda, MD 20892 USA
| | - Michael J Betenbaugh
- Department of Chemical & Biomolecular Engineering, Johns Hopkins University, 3400 North Charles Street, Baltimore, MD 21218-2686 USA
| | - Emily J Gallagher
- Division of Endocrinology, Diabetes and Bone Diseases, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, Box 1055, New York, NY 10029 USA
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Bowers LW, Rossi EL, O’Flanagan CH, deGraffenried LA, Hursting SD. The Role of the Insulin/IGF System in Cancer: Lessons Learned from Clinical Trials and the Energy Balance-Cancer Link. Front Endocrinol (Lausanne) 2015; 6:77. [PMID: 26029167 PMCID: PMC4432799 DOI: 10.3389/fendo.2015.00077] [Citation(s) in RCA: 107] [Impact Index Per Article: 10.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/23/2015] [Accepted: 04/29/2015] [Indexed: 02/06/2023] Open
Abstract
Numerous epidemiological and pre-clinical studies have demonstrated that the insulin/insulin-like growth factor (IGF) system plays a key role in the development and progression of several types of cancer. Insulin/IGF signaling, in cooperation with chronic low-grade inflammation, is also an important contributor to the cancer-promoting effects of obesity. However, clinical trials for drugs targeting different components of this system have produced largely disappointing results, possibly due to the lack of predictive biomarker use and problems with the design of combination therapy regimens. With careful attention to the identification of likely patient responders and optimal drug combinations, the outcome of future trials may be improved. Given that insulin/IGF signaling is known to contribute to obesity-associated cancer, further investigation regarding the efficacy of drugs targeting this system and its downstream effectors in the obese patient population is warranted.
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Affiliation(s)
- Laura W. Bowers
- Department of Nutrition, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
| | - Emily L. Rossi
- Department of Nutrition, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
| | - Ciara H. O’Flanagan
- Department of Nutrition, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
| | | | - Stephen D. Hursting
- Department of Nutrition, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
- *Correspondence: Stephen D. Hursting, Department of Nutrition, University of North Carolina at Chapel Hill, 135 Dauer Drive, McGavran-Greenberg Hall, Chapel Hill, NC 27599, USA,
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Yan L, DeMars LC. Effects of a high-fat diet on spontaneous metastasis of Lewis lung carcinoma in plasminogen activator inhibitor-1 deficient and wild-type mice. PLoS One 2014; 9:e110869. [PMID: 25356654 PMCID: PMC4214820 DOI: 10.1371/journal.pone.0110869] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2014] [Accepted: 09/19/2014] [Indexed: 12/12/2022] Open
Abstract
This study investigated the effects of a high-fat diet on spontaneous metastasis of Lewis lung carcinoma (LLC) in plasminogen activator inhibitor-1 deficient (PAI-1−/−) and wild-type mice. The high-fat diet increased the number of pulmonary metastases by 60% (p<0.01), tumor cross-sectional area by 82% (p<0.05) and tumor volume by 130% (p<0.05) compared to the AIN93G diet. Deficiency in PAI-1 reduced the number of metastases by 35% (p<0.01) compared to wild-type mice. In mice fed the high-fat diet, PAI-1 deficiency reduced tumor cross-sectional area by 52% (p<0.05) and tumor volume by 61% (p<0.05) compared to their wild-type counterparts; however, PAI-1 deficiency affected neither area nor volume in mice fed the AIN93G diet. Adipose and plasma concentrations of PAI-1 were significantly higher in high-fat fed wild-type mice than in their AIN93G-fed counterparts. Adipose and plasma PAI-1 were not detectable in PAI-1−/− mice regardless of the diet. Mice deficient in PAI-1 showed significantly greater plasma concentrations of monocyte chemotactic protein-1, tumor necrosis factor-α, leptin, vascular endothelial growth factor, tissue inhibitor of metalloproteinase-1 and insulin compared to wild-type mice, indicating a compensatory overproduction of inflammatory cytokines, angiogenic factors and insulin in the absence of PAI-1. We conclude that PAI-1 produced by the host, including that by adipose tissue, promotes high-fat enhanced metastasis of LLC.
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Affiliation(s)
- Lin Yan
- Grand Forks Human Nutrition Research Center, United States Department of Agriculture, Agricultural Research Service, Grand Forks, North Dakota, United States of America
- * E-mail:
| | - Lana C. DeMars
- Grand Forks Human Nutrition Research Center, United States Department of Agriculture, Agricultural Research Service, Grand Forks, North Dakota, United States of America
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Levin ER. Extranuclear estrogen receptor's roles in physiology: lessons from mouse models. Am J Physiol Endocrinol Metab 2014; 307:E133-40. [PMID: 24895281 PMCID: PMC4101634 DOI: 10.1152/ajpendo.00626.2013] [Citation(s) in RCA: 40] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/18/2013] [Accepted: 04/10/2014] [Indexed: 12/22/2022]
Abstract
Steroid receptors exist and function in multiple compartments of cells in most organs. Although the functions and nature of some of these receptors is being defined, important aspects of receptor localization and signaling to physiology and pathophysiology have been identified. In particular, extranuclear sex steroid receptors have been found in many normal cells and in epithelial tumors, where they enact signal transduction that impacts both nongenomic and genomic functions. Here, I focus on the progress made in understanding the roles of extranuclear estrogen receptors (ER) in physiology and pathophysiology. Extranuclear ER serve as a model to selectively intervene with novel receptor reagents to prevent or limit disease progression. Recent novel mouse models and membrane ER-selective agonists also provide a better understanding of receptor pool cross-talk that results in the overall integrative actions of sex steroids.
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Affiliation(s)
- Ellis R Levin
- Departments of Medicine and Biochemistry, University of California-Irvine and Long Beach Veterans Affairs Medical Center, Long Beach, California
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The p85 regulatory subunit of PI3K mediates cAMP-PKA and insulin biological effects on MCF-7 cell growth and motility. ScientificWorldJournal 2014; 2014:565839. [PMID: 25114970 PMCID: PMC4119716 DOI: 10.1155/2014/565839] [Citation(s) in RCA: 32] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2014] [Revised: 06/17/2014] [Accepted: 06/18/2014] [Indexed: 12/29/2022] Open
Abstract
Recent studies have shown that hyperinsulinemia may increase the cancer risk. Moreover, many tumors demonstrate an increased activation of IR signaling pathways. Phosphatidylinositol 3-kinase (PI3K) is necessary for insulin action. In epithelial cells, which do not express GLUT4 and gluconeogenic enzymes, insulin-mediated PI3K activation regulates cell survival, growth, and motility. Although the involvement of the regulatory subunit of PI3K (p85α (PI3K)) in insulin signal transduction has been extensively studied, the function of its N-terminus remains elusive. It has been identified as a serine (S83) in the p85α (PI3K) that is phosphorylated by protein kinase A (PKA). To determine the molecular mechanism linking PKA to insulin-mediated PI3K activation, we used p85α (PI3K) mutated forms to prevent phosphorylation (p85A) or to mimic the phosphorylated residue (p85D). We demonstrated that phosphorylation of p85α (PI3K)S83 modulates the formation of the p85α (PI3K)/IRS-1 complex and its subcellular localization influencing the kinetics of the insulin signaling both on MAPK-ERK and AKT pathways. Furthermore, the p85α (PI3K)S83 phosphorylation plays a central role in the control of insulin-mediated cell proliferation, cell migration, and adhesion. This study highlights the p85α (PI3K)S83 role as a key regulator of cell proliferation and motility induced by insulin in MCF-7 cells breast cancer model.
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Xu CX, Zhu HH, Zhu YM. Diabetes and cancer: Associations, mechanisms, and implications for medical practice. World J Diabetes 2014; 5:372-380. [PMID: 24936258 PMCID: PMC4058741 DOI: 10.4239/wjd.v5.i3.372] [Citation(s) in RCA: 100] [Impact Index Per Article: 9.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/28/2013] [Revised: 02/07/2014] [Accepted: 04/17/2014] [Indexed: 02/05/2023] Open
Abstract
Both diabetes mellitus and cancer are prevalent diseases worldwide. It is evident that there is a substantial increase in cancer incidence in diabetic patients. Epidemiologic studies have indicated that diabetic patients are at significantly higher risk of common cancers including pancreatic, liver, breast, colorectal, urinary tract, gastric and female reproductive cancers. Mortality due to cancer is moderately increased among patients with diabetes compared with those without. There is increasing evidence that some cancers are associated with diabetes, but the underlying mechanisms of this potential association have not been fully elucidated. Insulin is a potent growth factor that promotes cell proliferation and carcinogenesis directly and/or through insulin-like growth factor 1 (IGF-1). Hyperinsulinemia leads to an increase in the bioactivity of IGF-1 by inhibiting IGF binding protein-1. Hyperglycemia serves as a subordinate plausible explanation of carcinogenesis. High glucose may exert direct and indirect effects upon cancer cells to promote proliferation. Also chronic inflammation is considered as a hallmark of carcinogenesis. The multiple drugs involved in the treatment of diabetes seem to modify the risk of cancer. Screening to detect cancer at an early stage and appropriate treatment of diabetic patients with cancer are important to improve their prognosis. This paper summarizes the associations between diabetes and common cancers, interprets possible mechanisms involved, and addresses implications for medical practice.
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Handelsman Y, Leroith D, Bloomgarden ZT, Dagogo-Jack S, Einhorn D, Garber AJ, Grunberger G, Harrell RM, Gagel RF, Lebovitz HE, McGill JB, Hennekens CH. Diabetes and cancer--an AACE/ACE consensus statement. Endocr Pract 2014; 19:675-93. [PMID: 23978590 DOI: 10.4158/ep13248.cs] [Citation(s) in RCA: 58] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
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Belardi V, Gallagher EJ, Novosyadlyy R, LeRoith D. Insulin and IGFs in obesity-related breast cancer. J Mammary Gland Biol Neoplasia 2013; 18:277-89. [PMID: 24154546 DOI: 10.1007/s10911-013-9303-7] [Citation(s) in RCA: 66] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/24/2013] [Accepted: 10/02/2013] [Indexed: 02/07/2023] Open
Abstract
Obesity and the Metabolic Syndrome are associated with multiple factors that may cause an increased risk for cancer and cancer-related mortality. Factors involved include hyperinsulinemia, hyperglycemia, hyperlipidemia and IGFs. Insulin resistance is also associated with alterations in the levels of proinflammatory cytokines, chemokines, adipokines (leptin, adiponectin) that may also be contributing factors. The insulin family of proteins is ubiquitously expressed and has pleiotropic effects on metabolism and growth. However insulin, IGF-1 and particularly IGF-2 have been identified as tumor promoters in multiple studies. Mouse models have focused on insulin and IGF-1 and their receptors as being involved in tumor progression and metastases. The role of the insulin receptor as either mediating the effects on tumors or as compensating for the insulin-like growth factor receptor has arisen. Its role has been supported by preclinical studies and the importance of insulin resistance and hyperinsulinemia in obesity and early diabetes. Since the focus of this review is the insulin-family we will focus on insulin, IGF-1 and IGF-2.
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Affiliation(s)
- Valentina Belardi
- Department of Endocrinology, University of Pisa, Via Paradisa 2, 50124, Pisa, Italy
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Hvid H, Blouin MJ, Birman E, Damgaard J, Poulsen F, Fels JJ, Fledelius C, Hansen BF, Pollak M. Treatment with insulin analog X10 and IGF-1 increases growth of colon cancer allografts. PLoS One 2013; 8:e79710. [PMID: 24260289 PMCID: PMC3832545 DOI: 10.1371/journal.pone.0079710] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2013] [Accepted: 09/24/2013] [Indexed: 12/28/2022] Open
Abstract
Obesity and type 2 diabetes are associated with an increased risk for development of certain forms of cancer, including colon cancer. The publication of highly controversial epidemiological studies in 2009 raised the possibility that use of the insulin analog glargine increases this risk further. However, it is not clear how mitogenic effects of insulin and insulin analogs measured in vitro correlate with tumor growth-promoting effects in vivo. The aim of this study was to examine possible growth-promoting effects of native human insulin, insulin X10 and IGF-1, which are considered positive controls in vitro, in a short-term animal model of an obesity- and diabetes-relevant cancer. We characterized insulin and IGF-1 receptor expression and the response to treatment with insulin, X10 and IGF-1 in the murine colon cancer cell line (MC38 cells) in vitro and in vivo. Furthermore, we examined pharmacokinetics and pharmacodynamics and monitored growth of MC38 cell allografts in mice with diet-induced obesity treated with human insulin, X10 and IGF-1. Treatment with X10 and IGF-1 significantly increased growth of MC38 cell allografts in mice with diet-induced obesity and we can therefore conclude that supra-pharmacological doses of the insulin analog X10, which is super-mitogenic in vitro and increased the incidence of mammary tumors in female rats in a 12-month toxicity study, also increase growth of tumor allografts in a short-term animal model.
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Affiliation(s)
- Henning Hvid
- Diabetes Research Unit, Novo Nordisk A/S, Maaloev, Denmark
- * E-mail:
| | - Marie-José Blouin
- Lady Davis Institute for Medical Research, Jewish General Hospital, Montreal, Quebec, Canada
| | - Elena Birman
- Lady Davis Institute for Medical Research, Jewish General Hospital, Montreal, Quebec, Canada
| | | | - Fritz Poulsen
- Diabetes Research Unit, Novo Nordisk A/S, Maaloev, Denmark
| | | | | | | | - Michael Pollak
- Lady Davis Institute for Medical Research, Jewish General Hospital, Montreal, Quebec, Canada
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Gallagher EJ, Alikhani N, Tobin-Hess A, Blank J, Buffin NJ, Zelenko Z, Tennagels N, Werner U, LeRoith D. Insulin receptor phosphorylation by endogenous insulin or the insulin analog AspB10 promotes mammary tumor growth independent of the IGF-I receptor. Diabetes 2013; 62:3553-60. [PMID: 23835331 PMCID: PMC3781483 DOI: 10.2337/db13-0249] [Citation(s) in RCA: 54] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Endogenous hyperinsulinemia and insulin receptor (IR)/IGF-I receptor (IGF-IR) phosphorylation in tumors are associated with a worse prognosis in women with breast cancer. In vitro, insulin stimulation of the IR increases proliferation of breast cancer cells. However, in vivo studies demonstrating that IR activation increases tumor growth, independently of IGF-IR activation, are lacking. We hypothesized that endogenous hyperinsulinemia increases mammary tumor growth by directly activating the IR rather than the IGF-IR or hybrid receptors. We aimed to determine whether stimulating the IR with the insulin analog AspB10 could increase tumor growth independently of IGF-IR signaling. We induced orthotopic mammary tumors in control FVB/n and hyperinsulinemic MKR mice, and treated them with the insulin analog AspB10, recombinant human IGF-I, or vehicle. Tumors from mice with endogenous hyperinsulinemia were larger and had greater IR phosphorylation, but not IGF-IR phosphorylation, than those from control mice. Chronic AspB10 administration also increased tumor growth and IR (but not IGF-IR) phosphorylation in tumors. IGF-I led to activation of both the IGF-IR and IR and probably hybrid receptors. Our results demonstrate that IR phosphorylation increases tumor growth, independently of IGF-IR/hybrid receptor phosphorylation, and warrant consideration when developing therapeutics targeting the IGF-IR, but not the IR.
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Affiliation(s)
- Emily Jane Gallagher
- Division of Endocrinology, Diabetes and Bone Diseases, Samuel Bronfman Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, New York
| | - Nyosha Alikhani
- Division of Endocrinology, Diabetes and Bone Diseases, Samuel Bronfman Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, New York
| | - Aviva Tobin-Hess
- Division of Endocrinology, Diabetes and Bone Diseases, Samuel Bronfman Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, New York
| | - Jeffrey Blank
- Division of Endocrinology, Diabetes and Bone Diseases, Samuel Bronfman Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, New York
| | - Nicholas J. Buffin
- Division of Endocrinology, Diabetes and Bone Diseases, Samuel Bronfman Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, New York
| | - Zara Zelenko
- Division of Endocrinology, Diabetes and Bone Diseases, Samuel Bronfman Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, New York
| | - Norbert Tennagels
- R&D Diabetes Division, Sanofi-Aventis Deutschland, Frankfurt am Main, Germany
| | - Ulrich Werner
- R&D Diabetes Division, Sanofi-Aventis Deutschland, Frankfurt am Main, Germany
| | - Derek LeRoith
- Division of Endocrinology, Diabetes and Bone Diseases, Samuel Bronfman Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, New York
- Corresponding author: Derek LeRoith,
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Lin HC, Kachingwe BH, Lin HL, Cheng HW, Uang YS, Wang LH. Effects of metformin dose on cancer risk reduction in patients with type 2 diabetes mellitus: a 6-year follow-up study. Pharmacotherapy 2013; 34:36-45. [PMID: 23864581 DOI: 10.1002/phar.1334] [Citation(s) in RCA: 30] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
STUDY OBJECTIVE To explore the effects of metformin dose on cancer risk reduction in patients with type 2 diabetes. DESIGN Population-based cohort study. DATA SOURCE National Health Insurance program Longitudinal Health Insurance Database. PATIENTS A total of 65,754 age- and gender-matched patients without diabetes and no previous cancer diagnosis were extracted from the database. MEASUREMENTS AND MAIN RESULTS We compared cancer risk among the subjects who had no diabetes, had type 2 diabetes but were not on diabetes drugs, used metformin only, used antidiabetic drugs other than metformin, or used metformin in combination with other antidiabetic drugs. Our results revealed dose-dependent effects of metformin on cancer risk and cancer onset times. A significant decrease in cancer risk was found in the monotherapy group who received more than 360 defined daily doses (DDDs) of metformin (hazard ratio [HR] 0.40, 95% confidence interval [CI] 0.24-0.66). The greatest decrease in cancer risk was observed in patients who took more than 1080 DDDs (HR 0.27, 95% CI 0.09-0.84). Significantly greater dose-dependent effects were seen in patients who used metformin in combination with other antidiabetic drugs. CONCLUSION The magnitude of cancer risk reduction and prolonged cancer onset times produced by metformin in patients with type 2 diabetes depended on the dose of metformin, regardless of whether metformin was used alone or combined with other antidiabetic drugs.
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Affiliation(s)
- Hsiu-Chen Lin
- Department of Pediatrics, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan; Department of Laboratory Medicine, Taipei Medical University Hospital, Taipei, Taiwan
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Iqbal MA, Siddiqui FA, Gupta V, Chattopadhyay S, Gopinath P, Kumar B, Manvati S, Chaman N, Bamezai RNK. Insulin enhances metabolic capacities of cancer cells by dual regulation of glycolytic enzyme pyruvate kinase M2. Mol Cancer 2013; 12:72. [PMID: 23837608 PMCID: PMC3710280 DOI: 10.1186/1476-4598-12-72] [Citation(s) in RCA: 84] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2013] [Accepted: 06/13/2013] [Indexed: 12/13/2022] Open
Abstract
Background Insulin is tightly associated with cancer progression; however, mechanistic insights into such observations are poorly understood. Recent studies show that metabolic transformation is critical to cancer cell proliferation. Here, we attempt to understand the role of insulin in promotion of cancer metabolism. To this end, the role of insulin in regulating glycolytic enzyme pyruvate kinase M2 (PKM2) was examined. Results We observed that insulin up-regulated PKM2 expression, through PI3K/mTOR mediated HIF1α induction, but significantly reduced PKM2 activity independent of this pathway. Drop in PKM2 activity was attributed to subunit dissociation leading to formation of low activity PKM2 oligomers, as assessed by density gradient centrifugation. However, tyrosine 105 phosphorylation of PKM2, known for inhibiting PKM2 activity, remained unaffected on insulin treatment. Interestingly, insulin-induced ROS was found responsible for PKM2 activity reduction. The observed changes in PKM2 status led to augmented cancer metabolism. Insulin-induced PKM2 up-regulation resulted in enhanced aerobic glycolysis as confirmed by PKM2 knockdown studies. Further, PKM2 activity reduction led to characteristic pooling of glycolytic intermediates and increased accumulation of NADPH; suggesting diversion of glucose flux towards macromolecular synthesis, necessary for cancer cell growth. Conclusion The study identifies new PKM2-mediated effects of insulin on cancer metabolism, thus, advancing the understanding of insulin’s role in cancer.
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Affiliation(s)
- Mohd Askandar Iqbal
- National Centre of Applied Human Genetics, School of Life Sciences, Jawaharlal Nehru University, New Delhi 110067, India
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Ferguson R, Gallagher E, Cohen D, Tobin-Hess A, Alikhani N, Novosyadlyy R, Haddad N, Yakar S, LeRoith D. Hyperinsulinemia promotes metastasis to the lung in a mouse model of Her2-mediated breast cancer. Endocr Relat Cancer 2013; 20:391-401. [PMID: 23572162 PMCID: PMC4093836 DOI: 10.1530/erc-12-0333] [Citation(s) in RCA: 40] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
The Her2 oncogene is expressed in ∼25% of human breast cancers and is associated with metastatic progression and poor outcome. Epidemiological studies report that breast cancer incidence and mortality rates are higher in women with type 2 diabetes. Here, we use a mouse model of Her2-mediated breast cancer on a background of hyperinsulinemia to determine how elevated circulating insulin levels affect Her2-mediated primary tumor growth and lung metastasis. Hyperinsulinemic (MKR(+/+)) mice were crossed with doxycycline-inducible Neu-NT (MTB/TAN) mice to produce the MTB/TAN/MKR(+/+) mouse model. Both MTB/TAN and MTB/TAN/MKR(+/+) mice were administered doxycycline in drinking water to induce Neu-NT mammary tumor formation. In tumor tissues removed at 2, 4, and 6 weeks of Neu-NT overexpression, we observed increased tumor mass and higher phosphorylation of the insulin receptor/IGF1 receptor, suggesting that activation of these receptors in conditions of hyperinsulinemia could contribute to the increased growth of mammary tumors. After 12 weeks on doxycycline, although no further increase in tumor weight was observed in MTB/TAN/MKR(+/+) compared with MTB/TAN mice, the number of lung metastases was significantly higher in MTB/TAN/MKR(+/+) mice compared with controls (MTB/TAN/MKR(+/+) 16.41±4.18 vs MTB/TAN 5.36±2.72). In tumors at the 6-week time point, we observed an increase in vimentin, a cytoskeletal protein and marker of mesenchymal cells, associated with epithelial-to-mesenchymal transition and cancer-associated fibroblasts. We conclude that hyperinsulinemia in MTB/TAN/MKR(+/+) mice resulted in larger primary tumors, with more mesenchymal cells and therefore more aggressive tumors with more numerous pulmonary metastases.
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Rostoker R, Bitton-Worms K, Caspi A, Shen-Orr Z, LeRoith D. Investigating new therapeutic strategies targeting hyperinsulinemia's mitogenic effects in a female mouse breast cancer model. Endocrinology 2013; 154:1701-10. [PMID: 23515289 DOI: 10.1210/en.2012-2263] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/19/2022]
Abstract
Epidemiological and experimental studies have identified hyperinsulinemia as an important risk factor for breast cancer induction and for the poor prognosis in breast cancer patients with obesity and type 2 diabetes. Recently it was demonstrated that both the insulin receptor (IR) and the IGF-IR mediate hyperinsulinemia's mitogenic effect in several breast cancer models. Although IGF-IR has been intensively investigated, and anti-IGF-IR therapies are now in advanced clinical trials, the role of the IR in mediating hyperinsulinemia's mitogenic effect remains to be clarified. Here we aimed to explore the potential of IR inhibition compared to dual IR/IGF-IR blockade on breast tumor growth. To initiate breast tumors, we inoculated the mammary carcinoma Mvt-1 cell line into the inguinal mammary fat pad of the hyperinsulinemic MKR female mice, and to study the role of IR, we treated the mice bearing tumors with the recently reported high-affinity IR antagonist-S961, in addition to the well-documented IGF-IR inhibitor picropodophyllin (PPP). Although reducing IR activation, with resultant severe hyperglycemia and hyperinsulinemia, S961-treated mice had significantly larger tumors compared to the vehicle-treated group. This effect maybe secondary to the severe hyperinsulinemia mediated via the IGF-1 receptor. In contrast, PPP by partially inhibiting both IR and IGF-IR activity reduced tumor growth rate with only mild metabolic consequences. We conclude that targeting (even partially) both IR and IGF-IRs impairs hyperinsulinemia's effects in breast tumor development while simultaneously sparing the metabolic abnormalities observed when targeting IR alone with virtual complete inhibition.
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MESH Headings
- Animals
- Breast Neoplasms/complications
- Breast Neoplasms/genetics
- Breast Neoplasms/pathology
- Breast Neoplasms/therapy
- Carcinoma/complications
- Carcinoma/genetics
- Carcinoma/pathology
- Carcinoma/therapy
- Cell Line, Tumor
- Cell Proliferation/drug effects
- Disease Models, Animal
- Female
- Growth Substances/adverse effects
- Hyperinsulinism/complications
- Hyperinsulinism/drug therapy
- Hyperinsulinism/genetics
- Hyperinsulinism/pathology
- Insulin/adverse effects
- Mammary Neoplasms, Experimental/complications
- Mammary Neoplasms, Experimental/genetics
- Mammary Neoplasms, Experimental/pathology
- Mammary Neoplasms, Experimental/therapy
- Mice
- Mice, Transgenic
- Molecular Targeted Therapy/methods
- Peptides/therapeutic use
- Podophyllotoxin/analogs & derivatives
- Podophyllotoxin/therapeutic use
- Receptor, IGF Type 1/antagonists & inhibitors
- Receptor, IGF Type 1/genetics
- Therapies, Investigational/methods
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Affiliation(s)
- Ran Rostoker
- Diabetes and Metabolism Clinical Research Center of Excellence, Clinical Research Institute at Rambam and the Faculty of Medicine, Technion, Haifa, Israel
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50
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Alikhani N, Ferguson RD, Novosyadlyy R, Gallagher EJ, Scheinman E, Yakar S, LeRoith D. Mammary tumor growth and pulmonary metastasis are enhanced in a hyperlipidemic mouse model. Oncogene 2013; 32:961-7. [PMID: 22469977 PMCID: PMC4063440 DOI: 10.1038/onc.2012.113] [Citation(s) in RCA: 107] [Impact Index Per Article: 8.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2011] [Revised: 02/14/2012] [Accepted: 02/24/2012] [Indexed: 12/16/2022]
Abstract
Dyslipidemia has been associated with an increased risk for developing cancer. However, the implicated mechanisms are largely unknown. To explore the role of dyslipidemia in breast cancer growth and metastasis, we used the apolipoprotein E (ApoE) knockout mice (ApoE(-/-)), which exhibit marked dyslipidemia, with elevated circulating cholesterol and triglyceride levels in the setting of normal glucose homeostasis and insulin sensitivity. Non-metastatic Met-1 and metastatic Mvt-1 mammary cancer cells derived from MMTV-PyVmT/FVB-N transgenic mice and c-Myc/vegf tumor explants respectively, were injected into the mammary fat pad of ApoE(-/-) and wild-type (WT) females consuming a high-fat/high-cholesterol diet and tumor growth was evaluated. ApoE(-/-) mice exhibited increased tumor growth and displayed a greater number of spontaneous metastases to the lungs. Furthermore, intravenous injection of Mvt-1 cells resulted in a greater number of pulmonary metastases in the lungs of ApoE(-/-) mice compared with WT controls. To unravel the molecular mechanism involved in enhanced tumor growth in ApoE(-/-) mice, we studied the response of Mvt-1 cells to cholesterol in vitro. We found that cholesterol increased Akt(S473) phosphorylation in Mvt-1 cells as well as cellular proliferation, whereas cholesterol depletion in the cell membrane abrogated Akt(S473) phosphorylation induced by exogenously added cholesterol. Furthermore, in vivo administration of BKM120, a small-molecule inhibitor of phosphatidylinositol 3-kinase (PI3K), alleviated dyslipidemia-induced tumor growth and metastasis in Mvt-1 model with a concomitant decrease in PI3K/Akt signaling. Collectively, we suggest that the hypercholesterolemic milieu in the ApoE(-/-) mice is a favorable setting for mammary tumor growth and metastasis.
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Affiliation(s)
- Nyosha Alikhani
- Division of Endocrinology, Diabetes and Bone Diseases, The Samuel Bronfman Department of Medicine, Mount Sinai School Medicine, New York, New York
| | - Rosalyn D Ferguson
- Division of Endocrinology, Diabetes and Bone Diseases, The Samuel Bronfman Department of Medicine, Mount Sinai School Medicine, New York, New York
| | - Ruslan Novosyadlyy
- Division of Endocrinology, Diabetes and Bone Diseases, The Samuel Bronfman Department of Medicine, Mount Sinai School Medicine, New York, New York
| | - Emily Jane Gallagher
- Division of Endocrinology, Diabetes and Bone Diseases, The Samuel Bronfman Department of Medicine, Mount Sinai School Medicine, New York, New York
| | - Eyal Scheinman
- Diabetes and Metabolism Clinical Research Center of Excellence, Clinical Research Institute at Rambam (CRIR), Israel
| | - Shoshana Yakar
- Division of Endocrinology, Diabetes and Bone Diseases, The Samuel Bronfman Department of Medicine, Mount Sinai School Medicine, New York, New York
| | - Derek LeRoith
- Division of Endocrinology, Diabetes and Bone Diseases, The Samuel Bronfman Department of Medicine, Mount Sinai School Medicine, New York, New York
- Diabetes and Metabolism Clinical Research Center of Excellence, Clinical Research Institute at Rambam (CRIR), Israel
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