MCT-1 expression and PTEN deficiency synergistically promote neoplastic multinucleation through the Src/p190B signaling activation

• Published in: Oncogene Vol. 33; no. 43; pp. 5109 - 5120
• Main Authors: Wu, M-H, Chen, Y-A, Chen, H-H, Chang, K-W, Chang, I-S, Wang, L-H, Hsu, H-L
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 23.10.2014; Nature Publishing Group
• Subjects: 13; 13/1; 13/105; 14; 14/19; 38; 38/109; 38/77; 45; 49; 631/326/171; 64; 64/60; 82; 82/51; 96; 96/95; Animals; Apoptosis; Breast cancer; Breast Neoplasms - genetics; Breast Neoplasms - pathology; Cell Biology; Cell Line, Tumor; Cell Nucleus - metabolism; Cellular signal transduction; Female; Gene expression; Gene Expression Regulation, Neoplastic; Genetic aspects; GTPase-Activating Proteins - metabolism; Health aspects; Human Genetics; Humans; Internal Medicine; MCF-7 Cells; Medicine; Medicine & Public Health; Mice; Oncogene Proteins - genetics; Oncogene Proteins - metabolism; Oncogenes; Oncology; Original; original-article; Physiological aspects; Proto-Oncogene Proteins pp60(c-src) - metabolism; PTEN Phosphohydrolase - genetics; PTEN Phosphohydrolase - metabolism; rhoA GTP-Binding Protein - metabolism; Signal Transduction; Tumors
• ISSN: 0950-9232; 1476-5594
• DOI: 10.1038/onc.2014.125

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 ( m ultiple  c opies 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.