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

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.

• Authors: Yukari Okita, Minori Kimura, Rudy Xie, Chen Chen, Larina Tzu-Wei Shen, Yurika Kojima, Hiroyuki Suzuki, Masafumi Muratani, Masao Saitoh, Kentaro Semba, Carl-Henrik Heldin, Mitsuyasu Kato
• Journal: Science signaling (Sci Signal) Vol. 10 Issue 474 (Apr 11 2017) ISSN: 1937-9145 [Electronic] United States
• PMID: 28400538 (Publication Type: Journal Article)
• Copyright: Copyright © 2017, American Association for the Advancement of Science.

Chemical References

• GPNMB protein, human
• MAFK protein, human
• MafK Transcription Factor
• Membrane Glycoproteins

Topics

• Animals
• Cell Line, Tumor
• Disease Progression
• Epithelial-Mesenchymal Transition (genetics)
• Female
• Gene Expression Regulation, Neoplastic
• Humans
• Immunoblotting
• MCF-7 Cells
• MafK Transcription Factor (genetics, metabolism)
• Mammary Neoplasms, Experimental (genetics, metabolism, pathology)
• Membrane Glycoproteins (genetics, metabolism)
• Mice
• Neoplasm Invasiveness
• RNA Interference
• Reverse Transcriptase Polymerase Chain Reaction
• Triple Negative Breast Neoplasms (genetics, metabolism, pathology)
• Tumor Burden (genetics)