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 alpha)-positive breast tumors in premenopausal women. However resistance to tamoxifen occurs in many patients. ER alpha still plays a critical role in the growth of breast cancer cells with acquired tamoxifen resistance, suggesting that ER alpha remains a valid target for treatment of tamoxifen-resistant breast cancer. In an effort to identify novel regulators of ER alpha signaling, through a small-scale siRNA screen against histone methyl modifiers, we found WHSC1, a histone H3K36 methyltransferase, as a positive regulator for ER alpha signaling in breast cancer cells. We demonstrated that WHSC1 is recruited to the ER alpha gene by interacting with the BET protein BRD3/4, and facilitates ER alpha gene expression. The small-molecule BET protein inhibitor JQ1 potently suppressed the classic ER alpha signaling pathway and the growth of tamoxifen-resistant breast cancer cells in culture. Through the second year of funding, we have made the following discovery: 1. We have successfully dissected the molecular mechanisms of how WHSC1 complexes with BET proteins, and subsequently regulates the ER alpha gene expression at the chromatin level; 2. We have shown that JQ1 has potent anti-tumor activity against tamoxifen-resistant and estrogen deprivation- resistant breast cancer cells in multiple endocrine-resistant models; 3. We have demonstrated that in vivo, JQ1 has anti-cancer activity against tamoxifen-resistant tumor; most importantly, we have demonstrated that JQ1 potently inhibits growth of tamoxifen-resistant tumor in vivo when combined with fulvestrant therapy.
Document Details
- Document Type
- Technical Report
- Publication Date
- Jun 01, 2015
- Accession Number
- ADA620533
Entities
People
- Qin Feng
Organizations
- Baylor College of Medicine