Supplemental Estrogen Protects Against Obesity Induced Mammary Gland Inflammation In Mice

Obesity is a risk factor for the development of several malignancies including hormone receptor-positive breast cancer in postmenopausal women and has been associated with an increased risk of recurrence and reduced survival. A link between obesity, breast inflammation and hormone receptor-positive breast cancer was unknown. Obesity causes subclinical inflammation in visceral and subcutaneous white adipose tissue (WAT), characterized by macrophages surrounding dead or dying adipocytes forming crown-like structures (CLS). Estrogen synthesis is catalyzed by aromatase. Previously, we demonstrated CLS and elevated levels of pro-inflammatory mediators and aromatase in the mammary glands (MG) of obese mice and breast tissue of obese women. Recent clinical data suggests that supplemental estrogen given as monotherapy may reduce the risk of breast cancer. Here we tested the hypothesis that supplemental estrogen could prevent or reverse WAT inflammation (WATi) and related molecular changes in the MG of mice. In a prevention study, female C57BL/6J mice were ovariectomized (OVX) to simulate the postmenopausal state. The OVX mice received subcutaneous 17β estradiol (E2) or placebo prior to being initiated on a high fat diet (HFD). E2 supplementation protected mice against HFD-induced weight gain at least, in part, by suppressing caloric consumption. Suppression of weight gain was associated with a marked decrease in MG WATi (CLS/cm2) and a corresponding reduction in adipocyte diameter. Furthermore, expression of pro-inflammatory mediators (Cox-2, TNF-α, IL-1β) and aromatase were also reduced in the MG of mice that received supplemental E2. Next, to determine whether E2 supplementation can also reverse WATi, obese OVX mice were treated with either E2 or placebo and then continued on HFD. E2 supplementation led to physiologically relevant concentrations of 17β estradiol and caused weight loss along with a reversal in MG inflammation (CLS/cm2). Caloric consumption, adipocyte hypertrophy and MG expression of pro-inflammatory mediators and aromatase were also reduced with E2 treatment. Finally, we determined whether the protective effects of E2 were mediated by estrogen receptor-α (ERα), which has been suggested to play a key role in metabolic processes. Interestingly, ovary intact ERα knockout mice gained more weight and consumed more calories than HFD fed ovary intact wild-type mice. These changes were paralleled by adipocyte hypertrophy, WATi and elevated levels of pro-inflammatory mediators and aromatase in the MG. Collectively, our findings indicate that estrogen via ERα protects against weight gain, CLS formation and associated increases in pro-inflammatory mediators and aromatase in the MG. Whether similar effects occur in women warrants further investigation. Citation Format: Priya Bhardwaj, Baoheng Du, Xi Kathy Zhou, Erika Sue, Dilip Giri, Michael D. Harbus, Domenick J. Falcone, Clifford A. Hudis, Kotha Subbaramaiah, Andrew J. Dannenberg. Supplemental estrogen protects against obesity induced mammary gland inflammation in mice. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2876. doi:10.1158/1538-7445.AM2015-2876