Of the almost 240,000 new breast cancers diagnosed in 2011 within the USA, approximately 70% of these cases express the estrogen receptor-α (ER). ER targeted therapies such as tamoxifen (TAM) or faslodex (ICI) are often used to treat this breast cancer subtype. However, the curative potential of these interventions is frequently limited in patients due to resistance. Understanding how antiestrogen resistance occurs could lead to improved approaches to eradicate ER+ breast cancers. Increased unfolded protein response (UPR, an endoplasmic reticulum stress pathway) or autophagy (a “self” eating process used to clear dysfunctional protein or organelles) was previously shown to promote antiestrogen resistance in ER+ breast cancer. Using the antiestrogen sensitive MCF7-LCC1 (LCC1) and resistant MCF7-LCC9 (LCC9) cell lines, we determined the effect of antiestrogens and ERα on autophagy and UPR signaling. Suprisingly, ablation of ERα through RNAi potentiated LCC1 to antiestrogen-mediated cell death and resensitized LCC9 cells to endocrine therapy. While ICI stimulated both autophagy and UPR signaling, RNAi knockdown of ERα in LCC1 and LCC9 cells inhibited ICI-mediated UPR signaling and concurrently stimulated autophagy. Furthermore, we showed that ERα knockdown stimulated ROS production and potentiated the cell death response to antiestrogen therapy. ERα knockdown, but not ICI treatment, reduced nuclear Nrf2 (a UPR-induced antioxidant signaling protein) and increased cytosolic KEAP1 (an inhibitor of Nrf2), which may lead to the observed increase in ROS production. Autophagy inhibition through ATG7 silencing increases cell death and apoptosis in LCC1 ERα knockdown cells, showing that autophagy induction by antiestrogens is prosurvival in this context. These data suggests that UPR and autophagy stimulated by antiestrogen therapy results from two different mechanisms of ER regulation. We show that antiestrogens promote the accumulation of ERα in the cytosol that is associated with increased UPR signaling, while the inhibition of ERα promotes prosurvival autophagy. The inherent stimulation of resistance mechanism signaling through antiestrogen treatment suggests that combining autophagy or UPR inhibitors with anti-estrogens may greatly reduce the development of acquired antiestrogen resistance in breast cancer.
Citation Format: Pamela A. Clarke, Katherine Cook, Rong Hu, Jessica L. Schwartz, Mones Abu-Asab, Anni Warri, Robert Clarke. Estrogen receptor-α coordinates the unfolded protein response,autophagy, and reactive oxygen species generation to regulate breast cancer survival. [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 4046. doi:10.1158/1538-7445.AM2013-4046