OR41-3 A Small Molecule Inhibitor Reveals a Novel Pathway of Estrogen Receptor α Action and Induces Regression of Breast Cancers

Program: Abstracts - Orals, Featured Poster Presentations, and Posters
Session: OR41-Sex Hormone Receptors in Development, Aging and Cancer: Omics Approaches
Monday, June 17, 2013: 11:15 AM-12:45 PM
Presentation Start Time: 11:45 AM
Room 121 (Moscone Center)
Neal D Andruska*, Xujuan Yang, Chengjian Mao, Mathew M Cherian, Lily Mahapatra, William Helferich and David J Shapiro
University of Illinois, Urbana, IL
Estrogens, acting via estrogen receptor α (ERα), stimulate cell proliferation and tumor growth. For a well-studied protein, such as ERα, it was unclear whether unbiased high throughput screening for small molecule modulators could lead to the identification of new pathways and coregulators of ERα, and promising new therapeutic candidates. We performed a pathway-directed unbiased screen of 150,000 small molecules for selective non-competitive inhibitors of 17β-estradiol (E2)-ERα induced gene expression, followed by evaluating hits for inhibition of E2-ERα induced cell proliferation. At 100 nM, the most promising compound, BHPI, completely inhibited E2 induced proliferation in ERα containing breast, ovarian and endometrial cancer cells with no effect at 10,000 nM in counterpart ERα negative cells. BHPI is effective in ERα-containing cancer cells whose growth is not stimulated by estrogens. Expression of ERα is sufficient to render a cell sensitive to BHPI. BHPI activates a major pathway not previously linked to ERα action. Elements of this pathway are activated as part of the E2-ERα proliferation signature. In ERα positive breast cancers, pathway activation correlates with early recurrence and reduced survival. BHPI independently inhibits E2-ERα mediated gene expression. ChIP shows that BHPI acts by inhibiting recruitment of ERα to regulatory regions of estrogen responsive genes. Its dual action enables BHPI to selectively inhibit proliferation of drug resistant ERα positive breast and ovarian cancer cells. In a mouse xenograft model, BHPI was not toxic and induced rapid regression of large tumors. These studies demonstrate the potential of targeted cell-based screening to reveal new pathways of action, coregulators and small molecule therapeutic candidates; even in a system as intensively studied as ERα positive breast cancer.

Nothing to Disclose: NDA, XY, CM, MMC, LM, WH, DJS

*Please take note of The Endocrine Society's News Embargo Policy at http://www.endo-society.org/endo2013/media.cfm

Sources of Research Support: NIH DK-017909