Multinucleation is associated with malignant neoplasm; however, the molecular mechanism underlying the nuclear abnormality remains unclear. Loss or mutation of PTEN is frequently implicated in the development of malignancies. We now demonstrate that increased expression of the oncogene MCT-1 antagonizes PTEN gene expression, protein stability and activation, thereby further promoting PI3K/AKT signaling and survival rate of the PTEN-deficient cells. MCT-1 interacts with p190B and Src in the triple negative breast cancer cells, supporting they are in proximity of the signaling complexes in vivo. MCT-1 overexpression and PTEN loss synergistically augmented the Src/p190B signaling function leading to inhibition of RhoA activity. Under such condition, the incidence of mitotic catastrophes including spindle multipolarity and cytokinesis failure were enhanced, driving a Src/p190B-dependent neoplastic multinucleation. Reduced MCT-1 expression by shRNA dramatically repressed the Src/p190B function and improved the nuclear structure, as well as suppressed tumorigenicity of the PTEN-null triple negative breast cancer cells. Consistent with the oncogenic effects in vitro, clinical evidence has confirmed that MCT-1 and p190B genes are highly expressed in human breast cancers. Accordingly, MCT-1 gene induction is recognized as a potentially indicator of breast tumor development. Abrogating MCT-1 function may be a promising strategy for treatment of the triple negative breast cancer involving aberrant activation of Src and/or dysfunction of PTEN.
