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 (ERalpha)-positive breast tumors in premenopausal women. However resistance to tamoxifen occurs in many patients. ERalpha still plays a critical role in the growth of breast cancer cells with acquired tamoxifen resistance, suggesting that ERalpha 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 methyl transferase, as a positive regulator for ERalpha signaling in breast cancer cells. We demonstrated that WHSC1 is recruited to the ERalpha gene by interacting with the BET protein BRD3/4, and facilitates ERalpha gene expression. The small-molecule BET protein inhibitor JQ1 potently suppressed the classic ERalpha signaling pathway and the growth of tamoxifen-resistant breast cancer cells in culture. By performing a comprehensive mechanistic study, we found that JQ1 targets both ERalpha and MYC pathways on cell cycle-related genes in tamoxifen-resistant breast cancer cells. In addition, using a tamoxifen-resistant breast cancer xenograft mouse model, we are the first to show the in vivo anti-breast cancer activity by JQ1 and a strong long-lasting effect of combination therapy with JQ1 and the ERa degrader fulvestrant.
Document Details
- Document Type
- Technical Report
- Publication Date
- Aug 01, 2016
- Accession Number
- AD1030552
Entities
People
- Qin Feng
Organizations
- Baylor College of Medicine