Abstract 507: ERβ1 decreases breast cancer cell survival by regulating the unfolded protein response

Proceedings: AACR Annual Meeting 2014; April 5-9, 2014; San Diego, CA Estrogen receptors (ERs) regulate cellular processes that influence the development and response of breast cancer to hormonal therapy. Unfolded protein response (UPR) has been identified as a key mechanism that determines endocrine responsiveness and cellular survival in breast cancer. UPR assists the cells to cope with the stress caused by the accumulation of unfolded proteins in the endoplasmic reticulum (ER). Although ERα is known to affect the cellular response to ER stress, the role of ERβ in regulating the UPR has not been investigated. Here we show that the wild-type ERβ (ERβ1) enhanced apoptosis in breast cancer cells in response to treatment with the ER stress inducers thapsigargin and bortezomib. Targeting the Bcl-2 in the ER of the ERβ1-expressing cells prevented the apoptosis induced by ER stress but not by non-ER stress apoptotic stimuli indicating that ERβ1 promotes ER stress-regulated apoptosis. ERβ1 promoted ER stress-induced apoptosis by suppressing the inositol-requiring enzyme-1 (IRE-1) pathway of the UPR. ERβ1 repressed the transcription of the IRE-1α gene and the subsequent splicing of the X-box binding protein-1 (XBP-1). These results suggest a potential role of ERβ1 in influencing stress and therapy response in breast cancer by regulating the UPR. Citation Format: Christoforos Thomas, Gayani Rajapaksa, Fotis Nikolos, Igor Bado, Jan-Ake Gustafsson. ERβ1 decreases breast cancer cell survival by regulating the unfolded protein response. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 507. doi:10.1158/1538-7445.AM2014-507