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

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 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.

FGFR1 underlies obesity-associated progression of estrogen receptor–positive breast cancer after estrogen deprivation

“…In Rag1-null mice, mammary adipose E2 was below detection ( Figure 3H), and differences were not found in circulating E2 between LFLS-and HFHS-fed mice (13.9 ± 3.7 pM vs. 10.5 ± 2.1 pM, respectively). This is consistent with our previous report in female rats after OVX, where plasma levels did not differ with obesity and adipose tissue levels were below detection limits, simulating an environment of aromatase inhibition (38); however, levels of estrogen below detectable amounts may still sufficiently activate ER in cancer cells (40).…”

“…Recently, FGFR1 was reported to interact with ER in the cytoplasm and nucleus of endocrine-resistant breast cancer cells, suggesting that ER remains functional through growth factor pathway activation, despite estrogen deprivation (14). Taken together, these observations support a dual-requirement hypothesis that we have previously presented (38,47), in which metabolic impairment associated with obesity converges with a positive energy balance following estrogen deprivation to form a tumor-promoting environment (Figure 7). To tackle this problem clinically, it may only be necessary to improve metabolic function, either pharmacologically or through exercise, or to prevent EWD-induced weight gain.…”

“…We have previously shown in a rat model of chemically induced mammary cancer that diet-induced obesity promotes the survival and growth of ER-positive tumors after the loss of ovarian estrogen production (36)(37)(38). To extend our work, we implanted MCF7 cells or a potentially novel ER-positive PDX (UCD12; ref.…”

“…Mouse and human adipose tissue were processed, and E2 was analyzed by LC-MS/MS according to our previously described methods (38).…”

A network pharmacology-based approach to explore potential targets of Caesalpinia pulcherima: an updated prototype in drug discovery

“…The membrane was blocked and incubated with respective primary antibodies (ER and EGFR) at 4 °C overnight. Blots were washed, incubated with HRP-conjugated secondary antibodies, developed using chemiluminescent solution (Immobilon Western, Millipore, USA) and scanned by using gel documentation system (Bio-Rad) 36,37 . After adaptation for 7 days, rats were randomly divided into 5 groups of six rats each.…”