Abstract 2955: Effect of the combined treatment of TRA-8, an agonistic DR5 antibody, and tamoxifen on breast cancer cells.

Proceedings: AACR 104th Annual Meeting 2013; Apr 6-10, 2013; Washington, DC Breast cancer affects an estimated 1.3 million women worldwide annually (Breast Cancer Res Tr 127(2): 541-7, 2011). Certain breast cancer cell types are resistant or become resistant to conventional chemotherapy (Cancer Sci 94: 15-21, 2003). The use of targeted therapy for the controlled killing of cancer cells has become clinically desirable to sensitize breast cancer to anti-cancer drugs. TRA-8, a death receptor 5 (DR5) agonistic antibody, has been shown to be effective in activating apoptosis in breast cancer cells (Molecular Cancer Res 9(4): 403-17, 2011). However, sensitivity to TRA-8 induced apoptosis is dependent on the breast cancer subtype (Clin Cancer Res 9: 3731-41, 2003). Tamoxifen (TMX) is known for its potency in the treatment of estrogen receptor (ER)-positive breast cancers, but some ER-positive breast cancers have developed resistance to TMX treatment (J. Natl. Cancer Inst, 96(12):926-35, 2004). TMX is an inhibitor of the ER-mediated cell growth pathway and TMX is also a calmodulin (CaM) antagonist. The goal of this study is to understand the effect of the combined treatment of TRA-8 and TMX on breast cancer cell apoptosis. We hypothesize that the combination treatment of TMX and TRA-8 will sensitize the ER-positive breast cancer cells to apoptosis. The ER-positive breast cancer cell lines: MCF-7 and T47D were treated with and without estradiol, and then treated with TRA-8 only, TMX only and combined TRA-8 and TMX. Results showed that both MCF-7 and T47D cells showed synergism between TMX and TRA-8 for the cells treated with estradiol, but showed antagonism for the cells without estradiol treatment. Co-immunoprecipitation experiments using a DR5 antibody demonstrated the interactions of CaM with DR5 in MCF-7 and T47D cell lines. The results suggested that TMX inhibited the estradiol activated ER cell growth pathway and the cross-talk between DR5-mediated apoptosis pathway and ER-mediated cell growth pathway contributed to the observed synergism between TMX and TRA-8 treatment for ER activated MCF-7 and T47D cells. The observed antagonism between TMX and TRA-8 treatment for ER inactivated MCF-7 and T47D cells could have resulted from TMX serving as a CaM antagonist to inhibit CaM-DR5 interactions and thus inhibit DR5-induced apoptosis. Results from this study provide the basis for further investigations of the role of CaM/DR5 binding in mediating breast cancer apoptosis and the cross-talk between DR5-mediated apoptosis and ER-mediated cell growth pathways, which may lead to the novel therapeutic strategies for breast cancer. Citation Format: Tiara Napier, Romone Fancy, Tong Zhou, John Mountz, Yuhua Song. Effect of the combined treatment of TRA-8, an agonistic DR5 antibody, and tamoxifen on breast cancer cells. [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 2955. doi:10.1158/1538-7445.AM2013-2955