The Androgen Receptor supports tumor progression after the loss of ovarian function in a preclinical model of obesity and breast cancer
| Autor: | Sonali Jindal, Rebecca M. Foright, Ann D. Thor, Erin D. Giles, Pepper Schedin, Steven M. Anderson, Peter Kabos, Elizabeth A. Wellberg, Robera Oljira, Susan M. Edgerton, Paul S. MacLean, Reema Wahdan-Alaswad, L. Allyson Checkley, Stevi J. Johnson, Greg Dooley, Ginger C. Johnson, Jennifer K. Richer |
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| Jazyk: | angličtina |
| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
Cancer Research Endocrinology Diabetes and Metabolism Estrogen receptor Mass Spectrometry chemistry.chemical_compound 0302 clinical medicine Endocrinology Testosterone Mammary tumor Immunohistochemistry Postmenopause Oncology Adipose Tissue Receptors Androgen 030220 oncology & carcinogenesis Benzamides Disease Progression Female Steroids medicine.medical_specialty medicine.drug_class Ovariectomy Antineoplastic Agents Breast Neoplasms Article 03 medical and health sciences Breast cancer Internal medicine Cell Line Tumor Nitriles Phenylthiohydantoin medicine Enzalutamide Animals Humans Obesity Endocrine and Autonomic Systems business.industry Interleukin-6 Ovary Mammary Neoplasms Experimental medicine.disease Rats Androgen receptor Disease Models Animal 030104 developmental biology chemistry Estrogen Tumor progression Cancer cell business Biomarkers Chromatography Liquid |
| Popis: | The androgen receptor (AR) has context-dependent roles in breast cancer growth and progression. Overall, high tumor AR levels predict a favorable patient outcome, but several studies have established a tumor promotional role for AR, particularly in supporting the growth of estrogen receptor positive (ER-positive) breast cancers after endocrine therapy. Our previous studies have demonstrated that obesity promotes mammary tumor progression after ovariectomy (OVX) in a rat model of postmenopausal breast cancer. Here, we investigated a potential role for AR in obesity-associated post-OVX mammary tumor progression after ovarian estrogen loss. In this model, we found that obese but not lean rats had nuclear localized AR in tumors that progressed three weeks after OVX, compared to those that regressed. AR nuclear localization is consistent with activation of AR-dependent transcription. Longer-term studies (8 weeks post-OVX) showed that AR nuclear localization and expression were maintained in tumors that had progressed, but AR expression was nearly lost in tumors that were regressing. The anti-androgen Enzalutamide effectively blocked tumor progression in obese rats by promoting tumor necrosis, and also prevented the formation of new tumors after OVX. Neither circulating nor mammary adipose tissue levels of the AR ligand testosterone were elevated in obese compared to lean rats; however, IL-6, which we previously reported to be higher in plasma from obese versus lean rats, sensitized breast cancer cells to low levels of testosterone. Our study demonstrates that, in the context of obesity, AR plays a role in driving ER-positive mammary tumor progression in an environment of low estrogen availability, and that circulating factors unique to the obese host, including IL-6, may influence how cancer cells respond to steroid hormones. |
| Databáze: | OpenAIRE |
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