期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2015
卷号：112
期号：15
页码：4737-4742
DOI：10.1073/pnas.1403685112
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：SignificanceLate-stage estrogen receptor (ER)-positive breast and ovarian cancers exhibit many regulatory alterations and therefore resist therapy. Our novel ER inhibitor, BHPI, stops growth and often kills drug-resistant ER+ cancer cells and induces rapid and substantial tumor regression in a mouse model of human breast cancer. BHPI distorts a normally protective estrogen-ER-mediated activation of the unfolded protein response (UPR) and elicits sustained UPR activation. The UPR cannot be deactivated because BHPI, acting at a second site, inhibits production of proteins that normally help turn it off. This persistent activation converts the UPR from protective to lethal. Targeting therapy-resistant ER-positive cancer cells by converting the UPR from cytoprotective to cytotoxic may hold significant therapeutic promise. Recurrent estrogen receptor (ER)-positive breast and ovarian cancers are often therapy resistant. Using screening and functional validation, we identified BHPI, a potent noncompetitive small molecule ER biomodulator that selectively blocks proliferation of drug-resistant ER-positive breast and ovarian cancer cells. In a mouse xenograft model of breast cancer, BHPI induced rapid and substantial tumor regression. Whereas BHPI potently inhibits nuclear estrogen-ER-regulated gene expression, BHPI is effective because it elicits sustained ER-dependent activation of the endoplasmic reticulum (EnR) stress sensor, the unfolded protein response (UPR), and persistent inhibition of protein synthesis. BHPI distorts a newly described action of estrogen-ER: mild and transient UPR activation. In contrast, BHPI elicits massive and sustained UPR activation, converting the UPR from protective to toxic. In ER+ cancer cells, BHPI rapidly hyperactivates plasma membrane PLC{gamma
关键词：estrogen receptor ; drug discovery ; breast cancer ; unfolded protein response ; ovarian cancer
