Targeting mdr1 and endocrine therapy-­resistant cancers through estrogen receptor

Estrogens, acting via estrogen receptor (ER), stimulate cell proliferation and are associated with the development of aggressive breast and ovarian cancers. Endoplasmic reticulum (EnR) stress signaling cascade, the unfolded protein response (UPR), has documented in various human cancers and diseases. However, the precise roles of UPR signaling in development of hormone-dependent gynecological cancers were unknown. Here we show that the activation of UPR prior to EnR stress, also known as the anticipatory UPR activation, is a new paradigm for estrogen-ER action. We found that 17-estradiol (E2), acting through ER, rapidly activates Phospholipase C (PLC) leading to the production of inositol triphosphate (IP3). The IP3 binds to and opens endoplasmic reticulum (EnR) IP3 receptors (IP3R) leading to extremely rapid (