The G(12) family proteins upregulate matrix metalloproteinase-2 via p53 leading to human breast cell invasion

Abstract

Although mounting evidence suggests a role for G(12) proteins, G(alpha 12) and G(alpha 13), in tumor progression, a direct role of G(12) proteins has not been determined. This study aims to elucidate the molecular mechanism for a tumorigenic and invasive potential of G(alpha 12) and G(alpha 13) in MCF10A human breast epithelial cells. Here, we report, for the first time, that G(alpha 12) and G(alpha 13) induce upregulation of matrix metalloproteinase (MMP)-2 leading to the invasive and migratory phenotypes in MCF10A cells. We further show that p53 is an important transcription factor for induction of MMP-2 transcriptional activation by G(alpha 12/13). G(alpha 12/13)-induced MMP-2 upregulation, invasion, and migration are dependent on the activation of Ras, Rac1, MKK3/6, p38, and Akt. Using human breast tissue samples, we demonstrate that the expression levels of G(alpha 12) and MMP-2 are strongly correlated with the pathogenically diagnosed cancer (P < 0.0001). Moreover, the expression of G(alpha 12) shows a strong correlation with that of MMP-2 in human breast cancer tissues, implicating the in vivo tumorigenic potential of G(alpha 12). Taken together, this study elucidated the role of G(12) proteins in regulating processes for MMP-2 expression and malignant phenotypic conversion of MCF10A human breast epithelial cells, providing a molecular basis for the promoting role of G(alpha 12) and G(alpha 13) in breast cell invasion.