Discrete Adaptive Responses to MEK Inhibitor in Subpopulations of Triple-Negative Breast Cancer

Area of Science:

• Cancer Biology
• Epigenetics
• Drug Resistance

Background:

• Triple-negative breast cancer (TNBC) exhibits heterogeneity with epithelial and mesenchymal phenotypes.
• SUM-229PE cells model this heterogeneity, with distinct gene expression despite genomic similarity.

Purpose of the Study:

• To investigate the epigenetic mechanisms driving differential gene expression and drug resistance in TNBC subpopulations.
• To identify therapeutic targets for overcoming resistance to MEK inhibitors like trametinib.

Main Methods:

• Chromatin immunoprecipitation sequencing (ChIP-seq) to analyze open chromatin and H3K27ac.
• Motif analysis to identify transcription factor binding sites.
• RNA interference (RNAi) and gene expression analysis.

Main Results:

• Trametinib treatment induced enhancer remodeling and AP-1 motif enrichment.
• JUNB transcription factor localized to subpopulation-specific open chromatin regions.
• Increased CXCR7 expression and KRAS amplification contributed to trametinib resistance and proliferation.

Conclusions:

• Cell identity influences transcription factor localization to enhancers, controlling gene expression.
• Adaptive and acquired changes, including CXCR7 upregulation and KRAS amplification, mediate resistance to trametinib.
• Inhibiting early transcriptional reprogramming could be a strategy to prevent drug resistance in TNBC.