The G12 family proteins upregulate matrix metalloproteinase-2 via p53 leading to human breast cell invasion.

Although mounting evidence suggests a role for G(12) proteins, G(α12) and G(α13), 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(α12) and G(α13) in MCF10A human breast epithelial cells. Here, we report, for the first time, that G(α12) and G(α13) 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(α12/13). G(α12/13)-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(α12) and MMP-2 are strongly correlated with the pathogenically diagnosed cancer (P < 0.0001). Moreover, the expression of G(α12) shows a strong correlation with that of MMP-2 in human breast cancer tissues, implicating the in vivo tumorigenic potential of G(α12). 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(α12) and G(α13) in breast cell invasion.