Research ArticleCancer

The transcription factor MAFK induces EMT and malignant progression of triple-negative breast cancer cells through its target GPNMB

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Sci. Signal.  11 Apr 2017:
Vol. 10, Issue 474, eaak9397
DOI: 10.1126/scisignal.aak9397

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New targets for stalling breast cancer metastasis

Triple-negative breast cancer (TNBC) is an aggressive tumor that often metastasizes and is difficult to treat. Okita et al. analyzed tumor tissue from TNBC patients and found that poor prognosis correlated with increased expression of the gene encoding the transcription factor MAFK and one of its targets, the gene encoding the glycoprotein GPNMB. In cultured cells and mouse models, suppressing the MAFK-GPNMB pathway in tumor cells decreased migration and the incidence of lung metastasis. The MAFK-GPNMB axis links the TGF-β pathway with the kinase SRC, two pathways that are difficult to target safely and effectively. The findings suggest that inhibiting the MAFK-GPNMB axis may be a promising strategy to slow TNBC progression.

Abstract

Triple-negative breast cancer (TNBC) is particularly aggressive and difficult to treat. For example, the transforming growth factor–β (TGF-β) pathway is implicated in TNBC progression and metastasis, but its opposing role in tumor suppression in healthy tissues and early-stage lesions makes it a challenging target. Therefore, additional molecular characterization of TNBC may lead to improved patient prognosis by informing the development and optimum use of targeted therapies. We found that musculoaponeurotic fibrosarcoma (MAF) oncogene family protein K (MAFK), a member of the small MAF family of transcription factors that are induced by the TGF-β pathway, was abundant in human TNBC and aggressive mouse mammary tumor cell lines. MAFK promoted tumorigenic growth and metastasis by 4T1 cells when implanted subcutaneously in mice. Overexpression of MAFK in mouse breast epithelial NMuMG cells induced epithelial-mesenchymal transition (EMT) phenotypes and promoted tumor formation and invasion in mice. MAFK induced the expression of the gene encoding the transmembrane glycoprotein nmb (GPNMB). Similar to MAFK, GPNMB overexpression in NMuMG cells induced EMT, tumor formation, and invasion, in mice, whereas knockdown of MAFK in tumor cells before implantation suppressed tumor growth and progression. MAFK and GPNMB expression correlated with poor prognosis in TNBC patients. These findings suggest that MAFK and its target gene GPNMB play important roles in the malignant progression of TNBC cells, offering potentially new therapeutic targets for TNBC patients.

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