Abstract 4874: Bisphenol A exposure negates tamoxifen-mediated chemoprevention in MMTV-erbB2 transgenic mice.

Abstract

Abstract Bisphenol A (BPA), the building block of polycarbonate plastics with estrogenic activity, is one of the most common chemicals people are exposed to in daily life. Increasing reports suggest a link between BPA exposure and increased breast cancer risk. Although the effect of early BPA exposure and breast cancer risk later in life has been extensively studied, whether this xenoestrogen interferes with hormonal therapeutic agents, such as tamoxifen, has hardly been documented. In this study, we tested the effect of BPA exposure on mammary tumor development and tamoxifen-mediated chemoprevention in MMTV-erbB2 transgenic mice. BPA (500 ng/kg in sesame oil) was administered daily by subcutaneous injection for 8 weeks, starting from 8 weeks of age. Citrate tamoxifen at a dose of 1 mg/kg/day was administered by oral gavage alone or in combination with BPA. Based on tumor latency, we found that BPA alone accelerated mammary tumor development whereas tamoxifen treatment profoundly delayed the tumorigenesis. A combination of tamoxifen-treatment and BPA exposure, however, significantly (p<0.01) interfered with tamoxifen-mediated prevention as indicated by a shortened tumor latency compared to the tamoxifen group. BrdU incorporation and whole mount analysis of mammary glands at 16 weeks showed that BPA or tamoxifen alone induced distinctive proliferative and inhibitory ductal growth respectively. A combination of tamoxifen and BPA exposure abrogated tamoxifen-mediated growth inhibition. Importantly, altered tumor development and morphogenesis in each group were accompanied by modified signaling in estrogen receptor (ER) and EGFR/erbB2 pathways in mammary tissues. BPA alone induced enhanced phosphorylation/activation of ERα, the receptor tyrosine kinases (erbB2, EGFR and erbB3) and downstream targets (AKT1, and ERK½). Protein and mRNA levels of ERα, cyclin D1, EGFR, erbB3, and c-myc were also increased. In contrast, tamoxifen inhibited the activation of both pathways, as indicated by decreased phosphorylation and expression of those markers. In the combination group BPA exposure blocked tamoxifen-mediated inhibition of ER and erbB2 signaling. Our results demonstrated that BPA exposure promotes erbB2-associated carcinogenesis and negates tamoxifen-mediated chemoprevention. The underlying mechanisms involve BPA-induced activation and crosstalk of ER and erbB2 pathways. Taken together, our data suggests that BPA exposure is a risk factor that may interfere with hormonal therapy, which is of great translational value. Citation Format: XiaoHe Yang, Zhikun Ma, Yunbo Jiang. Bisphenol A exposure negates tamoxifen-mediated chemoprevention in MMTV-erbB2 transgenic mice. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4874. doi:10.1158/1538-7445.AM2013-4874