Abstract 2087: Estrogen receptor beta sensitizes breast cancer cells to endoplasmic reticulum stress-regulated apoptosis

Abstract

Abstract Estrogen receptor beta (ERβ) as estrogen-regulated transcription factor is involved in the development of the normal mammary gland and affects the progression and the anti-estrogen resistance of breast cancer. Recent data connect this resistance with the activation of survival mechanisms including the unfolded protein response (UPR). The UPR assists the cells to cope with the stress induced upon accumulation of unfolded proteins in the endoplasmic reticulum (ER) named ER stress. Although estrogen receptor alpha (ERα) has been shown to alter the resistance of breast cancer cells to anti-estrogens by modulating the levels of ER stress, the role of ERβ in the regulation of the UPR has not been elucidated. Here we show that ERβ decreases the resistance of breast cancer cells to chemically-induced ER stress by altering the inositol-requiring enzyme-1 (IRE-1) pathway of the UPR. In particular, we found that induction in the expression of ERβ enhances apoptosis and upregulates the ER stress-regulated pro-apoptotic CHOP/GADD153 in MDA-MB-231 breast cancer cells in response to treatment with the ER stressor thapsigargin. ERβ induces apoptosis under ER stress by inhibiting the unconventional mRNA splicing of X-box binding protein-1 (XBP-1), and thus, attenuating the upregulation of the active transcription factor which reduces the load of unfolded proteins in the ER. These results suggest ERβ as a potential modulator of the resistance of breast cancer cells to ER stressors through regulating the UPR. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 2087. doi:10.1158/1538-7445.AM2011-2087