Accession Number:

AD1030552

Title:

Treatment of Endocrine-Resistant Breast Cancer with a Small Molecule c-Myc Inhibitor

Descriptive Note:

Technical Report,01 Jun 2013,31 May 2016

Corporate Author:

Baylor College of Medicine Houston United States

Personal Author(s):

Report Date:

2016-08-01

Pagination or Media Count:

38.0

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 BRD34, 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.

Subject Categories:

  • Medicine and Medical Research

Distribution Statement:

APPROVED FOR PUBLIC RELEASE