Treatment of Endocrine-Resistant Breast Cancer with a Small Molecule C-MYC Inhibitor
Abstract
Breast cancer is the most common cancer in women. Tamoxifen has been a front-line treatment for estrogen receptor alpha (ER )-positive breast tumors in premenopausal women. However resistance to tamoxifen occurs in many patients. ER still plays a critical role in the growth of breast cancer cells with acquired tamoxifen resistance, suggesting that ER remains a valid target for treatment of tamoxifen-resistant breast cancer. In an effort to identify novel regulators of ER signaling, through a small-scale siRNA screen against histone methyl modifiers, we found WHSC1, a histone H3K36 methyltransferase, as a positive regulator for ER signaling in breast cancer cells. We demonstrated that WHSC1 is recruited to the ER gene by interacting with the BET protein BRD3/4, and facilitates ER gene expression. The small-molecule BET protein inhibitor JQ1 potently suppressed the classic ER signaling pathway and the growth of tamoxifen-resistant breast cancer cells in culture. Through the first year of funding, we have made the following discovery: 1. JQ1 targets both ER and MYC pathways in Tamoxifen-resistant cells; 2. JQ1 exerts tumor suppression effect mainly through regulating cell cycle genes; 3. JQ1 gene signature correlates with better clinical outcomes; 4. Tamoxifen-resistant MCF7 cells are more sensitive to JQ1 treatment; and GATA3 appear to be one of determinants for JQ1 sensitivity.
Document Details
- Document Type
- Technical Report
- Publication Date
- Jun 01, 2014
- Accession Number
- ADA607899
Entities
People
- Qin Feng
Organizations
- Baylor College of Medicine