Accession Number:

AD1008455

Title:

Therapeutic Mechanism of BET Bromodomain Inhibitor in Breast

Descriptive Note:

Technical Report,15 Aug 2013,14 Aug 2015

Corporate Author:

Dana-Farber Cancer Institute Boston United States

Personal Author(s):

• Liu,Xiaole S.

Report Date:

2015-12-01

Pagination or Media Count:

35.0

Abstract:

Genomic profiling of the MCF7 breast cancer cell line using BRD4 ChIP-seq and DNase-seq revealed BRD4 ChIP-seq and DNase-seq to be highly similar. We discovered that the BET inhibitor JQ1 tends to be more effective in slowing the growth of basal rather than luminal breast cancer cell lines. The initial gene expression response of a basal breast cancer cell line, SUM159, on treatment with JQ1, is predominated by the down-regulation of gene expression and this down-regulation is highly associated with BRD4 occupied genomic loci. By 24h of JQ1 treatment secondary effects dominate the gene expression pattern and BRD4 binding no longer predicts gene expression changes. Long-term treatment of SUM159 with JQ1 results in this cell line becoming insensitive to JQ1 and adopting a gene expression pattern that is more luminal-like. Long-term exposure of SUM159 cells to JQ1 leads to drug resistance that is acquired through a mechanism that allows BRD4 to bind to chromatin in a bromodomain independent manner.

Descriptors:

• breast cancer
• cancer research
• inhibitors
• gene expression
• therapeutics

Subject Categories:

Distribution Statement:

APPROVED FOR PUBLIC RELEASE