Abstract 4790: Adult exposure to a soy-rich diet promotes mammary tumor development in MMTV-erbB-2 transgenic mice through induction of ER-erbB-2 crosstalk.

The impact of soy and soy isoflavones, such as genistein, on breast cancer risk remains controversial. Although meta-analysis of multiple studies suggests that soy intake may be associated with a small reduction in breast cancer risk, increasing reports show that soy/genistein may be deleterious to breast cancer under certain conditions. Therefore, it is urgent to identify the factors that may affect the safety and risk of soy/genistein on breast cancer. We tackled this clinically relevant problem by examining the effect of adult exposure to soy/genistein on a subgroup of breast cancers that are positive for both estrogen receptor (ER) and erbB-2. erbB-2 is a receptor tyrosine kinase that is frequently overexpressed in breast cancer. ER+/erbB-2+ breast cancer accounts for ∼15-20% of breast cancer. Available data suggest that low dose soy/genistein stimulates ER+ breast cancer cells. On the other hand, genistein, a well known tyrosine kinase inhibitor, may inhibit erbB-2 overexpressing cells. The effect soy/genistein on ER+/erbB-2+ breast cancer is a dilemmatic question to be addressed. In this study MMTV-erbB-2 transgenic mice fed an AIN-93G diet were switched to a soy-rich diet (Purina 5001) at 20 weeks of age. Mammary tumor development in these mice was compared to that in control mice on a lifelong AIN-93G diet. We found that the adult switch to a soy diet accelerated mammary tumor development in this model. Average tumor latency for the control and soy-exposed groups were 36 and 32 weeks, respectively. Whole mount analysis indicated that the soy-diet-switch induced proliferation in the mammary glands as indicated by increased BrdU incorporation and epithelial density. We also found that changes in signaling of ER and erbB-2 pathways were modest at 24 weeks but more evident at 32 weeks. The soy-diet-switch induced ERα expression and phosphorylation which led to increased expression of ER target genes, including c-myc, cyclin D1, and Bcl-2. These changes were accompanied by increased phosphorylation/activation of EGFR, erbB-2, erbB-3, AKT1, and ERK½. Expression of EGFR and erbB-3 was also increased. Although the mammary tumors developed in this model were ER negative, mammary epithelial cells in the premalignant tissues were ER+/erbB-2+. These results provide in vivo evidence that the soy-rich diet stimulates the proliferation of ER+/erbB-2+ mammary epithelial cells, suggesting that soy/genistein-associated estrogenic activity overrides its tyrosine kinase inhibitor activity, possibly through ER-erbB-2 crosstalk. Our data suggests that ER+/erbB-2+ breast cancer might be particularly vulnerable to the risk associated with adult exposure to soy/genistein, and therefore patients with ER+/erbB-2+ tumors should be alerted. Citation Format: XiaoHe Yang, Zhikun Ma. Adult exposure to a soy-rich diet promotes mammary tumor development in MMTV-erbB-2 transgenic mice through induction of ER-erbB-2 crosstalk. [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 4790. doi:10.1158/1538-7445.AM2013-4790