Abstract 2939: Novel molecular mechanism for estradiol-induced apoptosis that contrasts with cytotoxic chemotherapy-induced apoptosis in breast cancer.
Authors: Obiorah Ifeyinwa , Sengupta Surojeet , Jordan Virgil C. 
Published: August 2014

Abstract
Clinical studies support the use of physiologic estrogens in the treatment of estrogen receptor (ER) positive postmenopausal breast cancer as a salvage therapy [Ellis et al. JAMA. 2009 Aug 19;302:774-80]. Additionally, the use of conjugated equine estrogens in hysterectomised postmenopausal women reveals consistent reduction in the incidence and mortality from invasive breast cancer.[Anderson,GL,et al. Lancet Oncol 2012, 13:476-486]. Laboratory studies have demonstrated that estradiol (E2) induces apoptosis in long term estrogen deprived MCF-7 cells [Lewis et al. J Natl Cancer Inst 2005, 97:1746 - 1759]. However, the process of E2 induced apoptosis appears to be a slow process. We have recently identified the sequential mechanism that lies behind E2 induced apoptosis using long term estrogen deprived breast cancer cells [Arazi et al. Proc Natl Acad Sci USA. 2011]. However, very little is known about the apoptotic effect of cytotoxic chemotherapy in these cells. Our goal here is to elucidate the critical trigger point for estradiol induced apoptosis and explore differential gene expression in comparison to cytotoxic chemotherapy induced apoptosis. To determine the critical trigger point for E2 induced apoptosis, we used 4OHT to block the apoptotic effect of E2 and we discovered that unlike chemotherapy the trigger for apoptosis occurs after 24 hours of E2 exposure. Paclitaxel is mitotic spindle inhibitor used extensively in the treatment of breast cancer[Qin YY et al. PLoS One. 2011; 6:e26946]. Using cell proliferation assays, we have shown that paclitaxel rapidly inhibits the growth of MCF7:5C cells by 24 hours while E2 only causes growth inhibition of these cells after 72 hours. Differential regulation of apoptotic gene expression in response to paclitaxel in comparison to E2-induced apoptosis with a particular interest to the critical trigger time point was interrogated using polymerase chain reaction arrays. Identified genes related to apoptosis showed that paclitaxel selectively activated the tumor necrosis factor (TNF) superfamily including TNF receptor superfamily, member 10a (TNFRSF10A)and TNFRSF10B which are known to be activated by the ligand TNF-related apoptosis inducing ligand (TNFSF10/TRAIL),after 12hrs of treatment and causes death through the extramitochondrial pathway. Furthermore death receptor genes FAS, TNF and other TNF super family genes; LTA,LTB are activated at 24 hrs treatment with paclitaxel . In contrast E2 induces apoptosis by activating initially the mitochondrial pathway of apoptosis, which is evidenced by increased expression of BCL211; BIM) at 36 hrs of treatment. Following 48 hrs of treatment, the gene expression expands to involve p53 and death receptor genes FAS, TNFRSF21 and TNF. The involvement of both intrinsic and extrinsic mechanism in E2 induced apoptosis may play a role in the delayed apoptosis observed with E2.
Citation Format: Ifeyinwa Obiorah, Surojeet Sengupta, Virgil C. Jordan. Novel molecular mechanism for estradiol-induced apoptosis that contrasts with cytotoxic chemotherapy-induced apoptosis in breast cancer. [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 2939. doi:10.1158/1538-7445.AM2013-2939