title: MCT-1 expression and PTEN deficiency synergistically promote neoplastic multinucleation through the Src/p190B signaling activation.
abstract: Multinucleation is associated with malignant neoplasms; however, the molecular mechanism underlying the nuclear abnormality remains unclear. Loss or mutation of PTEN promotes the development of malignant tumors. We now demonstrate that increased expression of the oncogene MCT-1 (multiple copies in T-cell malignancy 1) antagonizes PTEN gene presentation, PTEN protein stability and PTEN functional activity, thereby further promoting phosphoinositide 3 kinase/AKT signaling, survival rate and malignancies of the PTEN-deficient cells. In the PTEN-null cancer cells, MCT-1 interacts with p190B and Src in vivo, supporting that they are in proximity of the signaling complexes. MCT-1 overexpression and PTEN loss synergistically augments the Src/p190B signaling function that leads to inhibition of RhoA activity. Under such a condition, the incidence of mitotic catastrophes including spindle multipolarity and cytokinesis failure is enhanced, driving an Src/p190B/RhoA-dependent neoplastic multinucleation. Targeting MCT-1 by the short hairpin RNA markedly represses the Src/p190B function, improves nuclear structures and suppresses xenograft tumorigenicity of the PTEN-null breast cancer cells. Consistent with the oncogenic effects in vitro, clinical evidence has confirmed that MCT-1 gene stimulation is correlated with p190B gene promotion and PTEN gene suppression in human breast cancer. Accordingly, MCT-1 gene induction is recognized as a potential biomarker of breast tumor development. Abrogating MCT-1 function may be a promising stratagem for management of breast cancer involving Src hyperactivation and/or PTEN dysfunction.
authors.affiliation: Institute of Molecular and Genomic Medicine, National Health Research Institutes, Taiwan, ROC.
authors.forename: M-H
authors.initials: MH
authors.lastname: Wu
authors.affiliation: Institute of Molecular and Genomic Medicine, National Health Research Institutes, Taiwan, ROC.
authors.forename: Y-A
authors.initials: YA
authors.lastname: Chen
authors.affiliation: Institute of Molecular and Genomic Medicine, National Health Research Institutes, Taiwan, ROC.
authors.forename: H-H
authors.initials: HH
authors.lastname: Chen
authors.affiliation: Institute of Population Health Science, National Health Research Institutes, Taiwan, ROC.
authors.forename: K-W
authors.initials: KW
authors.lastname: Chang
authors.affiliation: National Institute of Cancer Research and Division of Biostatistics and Bioinformatics, National Health Research Institutes, Taiwan, ROC.
authors.forename: I-S
authors.initials: IS
authors.lastname: Chang
authors.affiliation: Institute of Molecular and Genomic Medicine, National Health Research Institutes, Taiwan, ROC.
authors.forename: L-H
authors.initials: LH
authors.lastname: Wang
authors.affiliation: Institute of Molecular and Genomic Medicine, National Health Research Institutes, Taiwan, ROC.
authors.forename: H-L
authors.initials: HL
authors.lastname: Hsu
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000235:genetics / Q000473:pathology*; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000378:metabolism*; D005260:Female; D020690:GTPase-Activating Proteins / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D061986:MCF-7 Cells; D051379:Mice; D015513:Oncogene Proteins / Q000235:genetics* / Q000378:metabolism; D051059:PTEN Phosphohydrolase / Q000235:genetics* / Q000378:metabolism; D016392:Proto-Oncogene Proteins pp60(c-src) / Q000378:metabolism; D015398:Signal Transduction; D020742:rhoA GTP-Binding Protein / Q000378:metabolism
chemical_list: D020690:GTPase-Activating Proteins; D015513:Oncogene Proteins; D016392:Proto-Oncogene Proteins pp60(c-src); D051059:PTEN Phosphohydrolase; D020742:rhoA GTP-Binding Protein