Epigenetic modulation of FOXM1-gene interacting network by BET inhibitors in breast cancer.

Abstract

FOXM1 is a transcription factor that has been implicated in the genesis of several tumors by regulating the expression of genes involved in the mitotic process. Transcriptomic enrichment analysis was performed to evaluate deregulated pathways in breast cancer, and relapse-free survival associated with the upregulated genes of FOXM1 signature was explored using the KM Plotter online tool. Treatment with bromodomain and extraterminal (BET) inhibitor JQ1 was explored in breast cancer cell lines to evaluate FOXM1 by qPCR and proliferation by MTT colorimetric assays. The FOXM1 gene signature was clearly deregulated in breast cancer patients, particularly in the basal-like subgroup where it was linked with detrimental prognosis. Treatment with the BET inhibitor JQ1 reduced the expression of FOXM1, decreasing cell proliferation in a panel of cell lines, being more active in the basal-like subtype, MDA-MB-231 and HS-578T. Knockdown of FOXM1 or treatment with JQ1 reduced genes included in the FOXM1 signature. Similarly, genes downregulated by the FOXM1 small interfering RNA approach were associated with detrimental outcome in breast cancer patients. Finally, we observed that FOXM1 was amplified in the triple-negative breast cancer subtype in around 15% of patients. Our study demonstrates that activation of the FOXM1 pathway has a prognostic role in breast cancer. JQ1 can modulate the expression of the FOXM1-gene interacting network, opening the opportunity for the evaluation of this compound in breast cancer patients.