Abstract P5-05-08: Obesity suppresses estrogen receptor beta expression in breast cancer cells via a HER2-mediated pathway

Abstract

Abstract Purpose: Increased levels of estrogen receptor beta (ERb) are correlated with an improved breast cancer prognosis. Our preliminary data suggests that obesity may decrease ERβ expression in certain breast cancer subtypes and may contribute to the more aggressive disease associated with obesity. This study aims to elucidate a potential mechanism(s) mediating this suppression. Experimental Design: We utilized an in vitro model of obesity in which breast cancer cells were exposed to sera collected from postmenopausal breast cancer patients at the Cancer Therapy and Research Center at the University of Texas Health Science Center at San Antonio (UTHSCSA) and pooled by BMI category (obese (OB): ≥30 kg/m2; normal weight (NW): 18.5-24.9 kg/m2). Four human mammary tumor cell lines were used: SKBR3 (HER2 over-expressing, ERα negative), MCF-7 and ZR75 (ERα positive, HER2 negative) and MDA-MB-231 (triple negative), in addition to the mouse mammary tumor cell line, MMTV/neu (HER2 over-expressing). The effects of the sera on ERβ expression were assessed by qPCR. Protein expression levels were determined using Western blot analyses. Herceptin, a HER2 antagonist, was used to evaluate the role of HER2 in OB sera-induced ERβ modulation. Results: OB sera exposure led to lower ERβ expression in SKBR3 and MMTV/neu cells in comparison to NW. Treatment of the SKBR3 cells with Herceptin at the time of OB sera exposure resulted in a three-fold increase in ERβ expression. In contrast, there was only a small increase in SKBR3 cell ERβ expression when Herceptin was added to NW sera, suggesting that the effects of the OB sera may be mediated by HER2 activity. In support of this hypothesis, exposure to OB versus NW sera did not modulate ERβ expression in MDA-MB-231, MCF-7 and ZR75 cells, which have very low levels of HER2. Lapatinib, another HER2 antagonist, will be used to inhibit HER2 signaling in MMTV/neu cells. On-going studies utilizing siRNA to the HER2 receptor aim to elucidate the HER2-regulated pathways contributing to the ERβ suppressing effects of OB sera in SKBR3 cells. Conclusion: Based on our preliminary data, we hypothesize that obesity suppresses ERβ expression in breast cancer cells via a HER2-mediated pathway. Elucidation of the mechanism(s) mediating this effect could provide important insight into both the regulation of ERβ expression as well as how obesity promotes a more aggressive disease. Increased knowledge regarding the regulation of this effect may result in the identification of a new treatment target for the obese breast cancer patient population. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P5-05-08.