The Androgen Receptor Supports Tumor Progression After the Loss of Ovarian Function in a Preclinical Model of Obesity and Breast Cancer

Elizabeth A. Wellberg, L. Allyson Checkley, Erin D. Giles, Stevi J. Johnson, Robera Oljira, Reema Wahdan-Alaswad, Rebecca M. Foright, Greg Dooley, Susan M. Edgerton, Sonali Jindal, Ginger C. Johnson, Jennifer K. Richer, Peter Kabos, Ann D. Thor, Pepper Schedin, Paul S. MacLean, Steven M. Anderson

Research output: Contribution to journalArticle

3 Citations (Scopus)

Abstract

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 following ovarian estrogen loss. In this model, we found that obese but not lean rats had nuclear localized AR in tumors that progressed 3 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.

Original languageEnglish (US)
Pages (from-to)1-17
Number of pages17
JournalHormones and Cancer
DOIs
StateAccepted/In press - Jul 24 2017

Fingerprint

Androgen Receptors
Obesity
Breast Neoplasms
Neoplasms
Estrogen Receptors
Testosterone
Interleukin-6
Estrogens
Ovariectomy
Growth
Androgens
Adipose Tissue
Breast
Necrosis
Steroids
Outcome Assessment (Health Care)
Hormones
Ligands

Keywords

  • Adipose tissue
  • Androgen receptor
  • Breast cancer
  • Estradiol
  • IL-6
  • Obesity
  • Steroid hormone
  • Testosterone

ASJC Scopus subject areas

  • Endocrinology, Diabetes and Metabolism
  • Oncology
  • Endocrinology
  • Endocrine and Autonomic Systems
  • Cancer Research

Cite this

Wellberg, E. A., Checkley, L. A., Giles, E. D., Johnson, S. J., Oljira, R., Wahdan-Alaswad, R., ... Anderson, S. M. (Accepted/In press). The Androgen Receptor Supports Tumor Progression After the Loss of Ovarian Function in a Preclinical Model of Obesity and Breast Cancer. Hormones and Cancer, 1-17. https://doi.org/10.1007/s12672-017-0302-9

The Androgen Receptor Supports Tumor Progression After the Loss of Ovarian Function in a Preclinical Model of Obesity and Breast Cancer. / Wellberg, Elizabeth A.; Checkley, L. Allyson; Giles, Erin D.; Johnson, Stevi J.; Oljira, Robera; Wahdan-Alaswad, Reema; Foright, Rebecca M.; Dooley, Greg; Edgerton, Susan M.; Jindal, Sonali; Johnson, Ginger C.; Richer, Jennifer K.; Kabos, Peter; Thor, Ann D.; Schedin, Pepper; MacLean, Paul S.; Anderson, Steven M.

In: Hormones and Cancer, 24.07.2017, p. 1-17.

Research output: Contribution to journalArticle

Wellberg, EA, Checkley, LA, Giles, ED, Johnson, SJ, Oljira, R, Wahdan-Alaswad, R, Foright, RM, Dooley, G, Edgerton, SM, Jindal, S, Johnson, GC, Richer, JK, Kabos, P, Thor, AD, Schedin, P, MacLean, PS & Anderson, SM 2017, 'The Androgen Receptor Supports Tumor Progression After the Loss of Ovarian Function in a Preclinical Model of Obesity and Breast Cancer', Hormones and Cancer, pp. 1-17. https://doi.org/10.1007/s12672-017-0302-9
Wellberg, Elizabeth A. ; Checkley, L. Allyson ; Giles, Erin D. ; Johnson, Stevi J. ; Oljira, Robera ; Wahdan-Alaswad, Reema ; Foright, Rebecca M. ; Dooley, Greg ; Edgerton, Susan M. ; Jindal, Sonali ; Johnson, Ginger C. ; Richer, Jennifer K. ; Kabos, Peter ; Thor, Ann D. ; Schedin, Pepper ; MacLean, Paul S. ; Anderson, Steven M. / The Androgen Receptor Supports Tumor Progression After the Loss of Ovarian Function in a Preclinical Model of Obesity and Breast Cancer. In: Hormones and Cancer. 2017 ; pp. 1-17.
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