Targeting the Unfolded Protein Response in Hormone-Regulated Cancers

Recent studies established that hormonal pathways that are implicated in cancer regulate the UPR and provide survival benefits for cancer cells. Regulation of UPR has important phenotypic outcomes for breast and prostate cancer, both in the hormone-sensitive and hormone-therapy-resistant advanced stages. Among the UPR pathways, the inositol requiring enzyme (IRE)1 and protein kinase RNA-like ER kinase (PERK) arms are best studied and strongly implicated in both breast and prostate cancer. Recent development of small molecule drugs that interfere with these pathways, either alone or with drugs that are currently used in the clinic, are poised to make significant contributions to therapeutic options in breast and prostate cancer. Cancer cells exploit many of the cellular adaptive responses to support their survival needs. One of these is the unfolded protein response (UPR), a highly conserved signaling pathway that is mounted in response to endoplasmic reticulum (ER) stress. Recent work showed that steroid hormones, in particular estrogens and androgens, regulate the canonical UPR pathways in breast cancer (BCa) and prostate cancer (PCa). In addition, UPR has pleiotropic effects in advanced disease and development of therapy resistance. These findings implicate the UPR pathway as a novel target in hormonally regulated cancers in the clinic. Here, we review the potential therapeutic value of recently developed small molecule inhibitors of UPR in hormone regulated cancers. Cancer cells exploit many of the cellular adaptive responses to support their survival needs. One of these is the unfolded protein response (UPR), a highly conserved signaling pathway that is mounted in response to endoplasmic reticulum (ER) stress. Recent work showed that steroid hormones, in particular estrogens and androgens, regulate the canonical UPR pathways in breast cancer (BCa) and prostate cancer (PCa). In addition, UPR has pleiotropic effects in advanced disease and development of therapy resistance. These findings implicate the UPR pathway as a novel target in hormonally regulated cancers in the clinic. Here, we review the potential therapeutic value of recently developed small molecule inhibitors of UPR in hormone regulated cancers.