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

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-α (ER) positive breast cancer. Thus, we recently investigated how ERα can regulate autophagy and the unfolded protein response (Cook et al., FASEBJ, 2014). We showed that inhibiting ERα signaling stimulates autophagosome formation and flux. Moreover, we showed that ERα knockdown inhibited the unfolded protein response (UPR) signaling components. Here we support and extend this recent report showing additional data on ERα localization and provide a schematic of the overall signaling implicated by our results. Differential activation of UPR and autophagy highlight the pivotal role of ERα in regulating pro-survival signaling in breast cancer through UPR and autophagy. Furthermore, these data suggest new approaches to successful targeting ERα and preventing the regulation of key pro-survival signaling that confers resistance to endocrine therapies.