Understanding the Tumor Repressive Function of Estrogen Receptor Beta in Breast Cancer
Rajapaksa, R P Gayani Kumudu 1981-
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Estrogen receptors play a key role in breast cancer, and understanding the mechanisms of action is important in clinical management of the disease. Here we attempted to comprehend the role of the second estrogen receptor (ERβ) in two fundamental cellular mechanisms vital in the development and progression of breast cancer, unfolded protein response (UPR) and epithelial-to-mesenchymal transition (EMT). UPR confers therapeutic resistance and cellular survival in breast cancer in response to endoplasmic reticulum (EnR) stress that is induced by poorly vascularized tumor microenvironment. ERα regulates UPR-driven cell survival; however the role of ERβ is unknown. Here wild-type ERβ (ERβ1) decreased the survival of triple-negative and ERα-positive breast cancer cells in response to pharmacological stress inducers thapsigargin and bortezomib. ERβ1 enhanced cellular apoptosis by down regulating the UPR transducer inositol-requiring enzyme 1 (IRE1) and the splicing of X box-binding protein-1 (XBP-1). Further, expression of ERβ1 in EnR-stressed tamoxifen-resistant cells decreased survival by down regulating the IRE1/XBP-1s pathway. Interestingly, up regulation of ERβ1 increased the sensitivity of tamoxifen-resistant cells to tamoxifen, indicating the role of ERβ1 in regulating resistance of breast cancer to a variety of stressors including anti-estrogens through regulating the UPR. In addition, ERβ1 suppressed the activation of (PKR)-like endoplasmic reticulum kinase (PERK) pathway of UPR in breast cancer cells. Given the association of the PERK pathway with the inhibition of protein synthesis and the activation of pro-survival autophagy, ERβ1 may affect the survival of breast cancer cells by regulating the translational machinery and autophagy. In addition to the down regulation of UPR, ERβ1 was found to imbed EMT and decrease the invasiveness of breast cancer cells. ERβ1 inhibited EMT by up-regulating members of the microRNA-200 family and repressing transcriptional repressors (ZEB1, SIP1) leading to increased expression of epithelial marker E-cadherin. Furthermore, clinical breast cancer specimens showed a positive correlation between ERβ1 and E-cadherin, further supporting that ERβ1 regulates EMT and invasion in breast cancer. The repression of UPR and EMT by ERβ1 strongly supports its tumor suppressive role in breast cancer and suggests its potential utility as a prognostic marker and therapeutic target for the clinical management of the disease.