MT4-MMP Modulates the Expression of miRNAs in Breast Cancer Cells

Background: MT4-MMP is a member of the metalloproteinases family, although with a controversial role in the extracellular matrix remodelation. Overexpression of this metalloproteinase has been observed in breast cancer and it has been suggested that it can regulate tumor growth and cancer progression. The mechanisms by which MT4-MMP participates in breast cancer includes tumor blood vessels desestabilization, the activation of an angiogenic switch, and increase of EGFR signaling. However, all the mechanisms by which MT4-MMP participates in breast cancer are still unknowns.

Aim of the study: To study if MT4-MMP could modulate the expression of microRNAs (miRNAs) related to biological processes associated with tumor formation and progression.

Methods: MT4-MMP was ectopically overexpressed in MDA-MB-231 cells and the miRNAs expression profile modulated by the metalloproteinase was studied by using miRNAs microarrays. Microarray data were analyzed with different tools to find the molecular and cellular functions related to the differentially expressed miRNAs. The clinical relevance of some miRNAs was analyzed using a public database.

Results: MT4-MMP overexpression in breast cancer cells induced the modulation of 65 miRNAs, which were related to the alteration of pathways dependent of p53, TGF-β, MAPK, ErbB, and Wnt, as well as processes such as cell cycle, adherens junctions, apoptosis, and focal adhesion. Several of the upregulated miRNAs were associated to a worse prognosis in breast cancer patients.

Conclusions: In breast cancer cells, the overexpression of MT4-MMP modulates the expression of miRNAs involved in several biological processes associated with tumor formation and progression and with clinical relevance.