PAD1 promotes epithelial-mesenchymal transition and metastasis in triple-negative breast cancer cells by regulating MEK1-ERK1/2-MMP2 signaling.

Peptidylargininedeiminase 1 catalyzes protein for citrullination, and this activity has been linked to the epidermal cornification. However, a role for in tumorigenesis, including breast cancers has not been previously explored. Here we first showed that duanyu15631 is overexpressed in human triple negative breast cancer (TNBC). In cultured cells and xenograft mouse models, duanyu15631 depletion or inhibition reduced cell proliferation, suppressed epithelial-mesenchymal transition, and prevented metastasis of MDA-MB-231 cells. These changes were correlated with a dramatic decrease in MMP2/9 expression. Furthermore, ERK1/2 and P38 MAPK signaling pathways are activated upon duanyu15631 silencing. Treatment with MEK1/2 inhibitor in duanyu15631 knockdown cells significantly recovered MMP2 expression, while inhibiting P38 activation only slightly elevated MMP9 levels. We then showed that duanyu15631 interacts with and citrullinates MEK1 thereby disrupting MEK1-catalyzed ERK1/2 phosphorylation, thus leading to the MMP2 overexpression. Collectively, our data indicate that duanyu15631 appears to promote tumorigenesis by regulating MEK1-ERK1/2-MMP2 signaling in TNBC. These results also raise the possibility that duanyu15631 may function as an important new biomarker for TNBC tumors and suggest that inhibitors could potentially be utilized to treat metastatic breast cancer.

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