Abstract 4134: Breast cancer antiestrogen resistance-3 promotes growth in the presence of tamoxifen through a mechanism involving p130cas and c-src

Proceedings: AACR 101st Annual Meeting 2010‐‐ Apr 17‐21, 2010; Washington, DC Tamoxifen, an antiestrogen and estrogen receptor (ER) ligand, has been successfully used to treat ER-positive breast tumors for almost 40 years. For women with ER-positive disease, tamoxifen treatment can decrease the rate of recurrence by 50% and reduce the risk of death by 25%. Despite such success, resistance occurs in up to one-third of patients. To date, many proteins have been identified that contribute to resistance. Breast Cancer Antiestrogen Resistance-3 (BCAR3) is one such molecule; its expression induces resistance to the antiestrogens tamoxifen and ICI 182, 780 (fulvestrant). To investigate the signaling pathway(s) driving BCAR3-mediated resistance, we generated clones of the ER-positive and antiestrogen-sensitive MCF7 cell line that overexpress BCAR3 (MCF7 B6). Utilizing these cells, we show here that BCAR3 overexpression confers a growth advantage under conditions of both hormone deprivation and tamoxifen treatment. We further employed this inducible cell line to examine the relationship between BCAR3 and two other molecules that have been implicated in both antiestrogen resistance and BCAR3 signaling: the scaffold/adaptor molecule p130Cas (Cas, also known as BCAR1) and the non-receptor tyrosine kinase c-Src (Src). Upon BCAR3 overexpression, we observed an alternative Src-Cas complex, increased Src kinase activity, and an increase in Src-dependent tyrosine phosphorylation of Cas. Interestingly, these BCAR3-induced effects are preserved following tamoxifen treatment. Conversely, upon knockdown of BCAR3 in the ER-negative BT549 breast cancer cell line, Src activity was reduced, as were Cas phosphorylation and Src-Cas interactions. We also examined the expression and subcellular localization of the cyclin-dependent kinase inhibitor and known Src substrate, p27. In MCF7 B6 cells overexpressing BCAR3, we observed a decrease in the nuclear accumulation of p27 under conditions of both hormone deprivation and tamoxifen treatment. Based on these data and the established role of Src-Cas signaling in the induction of antiestrogen resistance, we postulate that these factors play a significant role in the promotion and establishment of BCAR3-mediated tamoxifen resistance. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 4134.