Estrogen receptor α inhibitor activates the unfolded protein response, blocks protein synthesis, and induces tumor regression
Abstract
Late-stage estrogen receptor α (ERα)-positive breast and ovarian cancers exhibit many regulatory alterations and therefore resist therapy. Our novel ERα inhibitor, BHPI, stops growth and often kills drug-resistant ERα + cancer cells and induces rapid and substantial tumor regression in a mouse model of human breast cancer. BHPI distorts a normally protective estrogen–ERα-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 ERα-positive cancer cells by converting the UPR from cytoprotective to cytotoxic may hold significant therapeutic promise.
Document Details
- Document Type
- Pub Defense Publication
- Publication Date
- Mar 30, 2015
- Source ID
- 10.1073/pnas.1403685112
Entities
People
- Chengjian Mao
- David J. Shapiro
- Lily Mahapatra
- Mathew M. Cherian
- Neal D. Andruska
- William G Helferich
- Xiaobin Zheng
- Xujuan Yang
Organizations
- National Cancer Institute
- National Institute of Diabetes and Digestive and Kidney Diseases
- Office of Dietary Supplements
- United States Department of Defense
- University of Illinois Urbana–Champaign