MicroRNA profiling identifies Forkhead box transcription factor M1 (FOXM1) regulated miR-186 and miR-200b alterations in triple negative breast cancer

Abstract

Breast cancer (BC) is the most commonly diagnosed malignancy. MicroRNAs (miRNAs) play important roles in the tumorigenesis, metastasis and progression of BC. Forkhead Box M1 (FOXM1) oncogenic transcription factor is involved in events considered as hallmarks of cancer. However, the specific mechanism by which FOXM1 exerts its oncogenic effects remains unclear and little is known about its effects on the regulation of miRNA expression. We have found that FOXM1 is upregulated in breast cancer cells and that its expression is associated with shortened overall survival and poor prognosis in patients with BC. Using microarray technology, we assessed the expression profiles of 752 miRNAs in highly aggressive and metastatic triple negative breast cancer (TNBC) cells in response to FOXM1 knockdown and identified 13 differentialy expressed miRNAs (3 miRNAs upregulated and 10 miRNAs down-regulated). We validated the results of the miRNA expression profile in two different TNBC cells by performing qRT-PCR and identified that miR-186-5p and miR-200b-5p were consistently down- or up-regulated, respectively, after knockdown of FOXM1. We further performed KEGG pathway analysis and GO enrichment analysis for miR-186-5p and miR-200b-5p, and identified that these miRNAs are associated with cancer development and progression involving toll-like receptor signaling, cell cycle, AMPK, p53 and NF-kappa B signaling pathways. Taken together, our results suggest that increased FOXM1 expression is associated with poor patient survival and leads to induction of oncomiR miR-186-5p expression and tumor-suppressor inhibition miR-200b-5p, suggesting that the FOXM1/miRNA signaling pathway may contribute to poor patient prognosis and may be a potential therapeutic target in TNBC.