Therapeutic approaches in young women with advanced or metastatic breast cancer

Although mounting evidence suggests a role for G₁₂ proteins, G_α12 and G_α13, in tumor progression, a direct role of G₁₂ 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 G₁₂ 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.