title: 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.MAFKandGPNMBexpression correlated with poor prognosis in TNBC patients. These findings suggest that MAFK and its target geneGPNMBplay important roles in the malignant progression of TNBC cells, offering potentially new therapeutic targets for TNBC patients.
authors.affiliation: Department of Experimental Pathology, Graduate School of Comprehensive Human Sciences and Faculty of Medicine, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki 305-8575, Japan.
authors.forename: Yukari
authors.identifier: http://orcid.org/0000-0002-7279-4634
authors.initials: Y
authors.lastname: Okita
authors.affiliation: Department of Experimental Pathology, Graduate School of Comprehensive Human Sciences and Faculty of Medicine, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki 305-8575, Japan.
authors.forename: Minori
authors.identifier: http://orcid.org/0000-0002-1535-4157
authors.initials: M
authors.lastname: Kimura
authors.affiliation: Department of Experimental Pathology, Graduate School of Comprehensive Human Sciences and Faculty of Medicine, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki 305-8575, Japan.
authors.forename: Rudy
authors.identifier: http://orcid.org/0000-0003-0011-8191
authors.initials: R
authors.lastname: Xie
authors.affiliation: Department of Experimental Pathology, Graduate School of Comprehensive Human Sciences and Faculty of Medicine, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki 305-8575, Japan.
authors.forename: Chen
authors.identifier: http://orcid.org/0000-0002-5215-3442
authors.initials: C
authors.lastname: Chen
authors.affiliation: Department of Experimental Pathology, Graduate School of Comprehensive Human Sciences and Faculty of Medicine, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki 305-8575, Japan.
authors.forename: Larina Tzu-Wei
authors.identifier: http://orcid.org/0000-0003-1389-6697
authors.initials: LT
authors.lastname: Shen
authors.affiliation: Department of Experimental Pathology, Graduate School of Comprehensive Human Sciences and Faculty of Medicine, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki 305-8575, Japan.
authors.forename: Yurika
authors.initials: Y
authors.lastname: Kojima
authors.affiliation: Department of Experimental Pathology, Graduate School of Comprehensive Human Sciences and Faculty of Medicine, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki 305-8575, Japan.
authors.forename: Hiroyuki
authors.identifier: http://orcid.org/0000-0003-2646-5132
authors.initials: H
authors.lastname: Suzuki
authors.affiliation: Department of Genome Biology, Graduate School of Comprehensive Human Sciences and Faculty of Medicine, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki 305-8575, Japan.
authors.forename: Masafumi
authors.identifier: http://orcid.org/0000-0002-0276-8000
authors.initials: M
authors.lastname: Muratani
authors.affiliation: Department of Biochemistry, Interdisciplinary Graduate School of Medicine and Engineering, University of Yamanashi, 1110 Shimokato, Chuo, Yamanashi 409-3898, Japan.
authors.forename: Masao
authors.identifier: http://orcid.org/0000-0002-2293-2330
authors.initials: M
authors.lastname: Saitoh
authors.affiliation: Department of Life Science and Medical Bioscience, School of Advanced Science and Engineering, Waseda University, 2-2 Wakamatsu-cho, Shinjuku, Tokyo 162-8480, Japan.
authors.forename: Kentaro
authors.identifier: http://orcid.org/0000-0001-7507-8214
authors.initials: K
authors.lastname: Semba
authors.affiliation: Ludwig Institute for Cancer Research, Science for Life Laboratory, Uppsala University, Box 595, SE-751 24 Uppsala, Sweden.
authors.forename: Carl-Henrik
authors.identifier: http://orcid.org/0000-0002-9508-896X
authors.initials: CH
authors.lastname: Heldin
authors.affiliation: Department of Experimental Pathology, Graduate School of Comprehensive Human Sciences and Faculty of Medicine, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki 305-8575, Japan. mit-kato@md.tsukuba.ac.jp.
authors.forename: Mitsuyasu
authors.identifier: http://orcid.org/0000-0001-9905-2473
authors.initials: M
authors.lastname: Kato
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D018450:Disease Progression; D058750:Epithelial-Mesenchymal Transition / Q000235:genetics*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D015151:Immunoblotting; D061986:MCF-7 Cells; D050985:MafK Transcription Factor / Q000235:genetics* / Q000378:metabolism; D008325:Mammary Neoplasms, Experimental / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D008562:Membrane Glycoproteins / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D009361:Neoplasm Invasiveness; D034622:RNA Interference; D020133:Reverse Transcriptase Polymerase Chain Reaction; D064726:Triple Negative Breast Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D047368:Tumor Burden / Q000235:genetics
chemical_list: C503042:GPNMB protein, human; C494695:MAFK protein, human; D050985:MafK Transcription Factor; D008562:Membrane Glycoproteins