Estrogen receptor-? signaling and localization regulates autophagy and unfolded protein response activation in ER+ breast cancer

Abstract

Antiestrogen therapy is commonly used to treat estrogen receptor (ER)+ breast cancers but acquired and de novo resistance limits their overall curative potential. An endoplasmic reticulum stress pathway, the unfolded protein response, and autophagy are both implicated in the development of antiestrogen therapy resistance in estrogen receptor-? (ER) positive breast cancer. Thus, we recently investigated how ER? can regulate autophagy and the unfolded protein response (Cook et al., FASEBJ, 2014). We showed that inhibiting ER? signaling stimulates autophagosome formation and flux. Moreover, we showed that ER? knockdown inhibited the unfolded protein response (UPR) signaling components. Here we support and extend this recent report showing additional data on ER? localization and provide a schematic of the overall signaling implicated by our results. Differential activation of UPR and autophagy highlight the pivotal role of ER? in regulating pro-survival signaling in breast cancer through UPR and autophagy. Furthermore, these data suggest new approaches to successful targeting ER? and preventing the regulation of key pro-survival signaling that confers resistance to endocrine therapies.