The [G.sub.12] family proteins upregulate matrix metalloproteinase-2 via p53 leading to human breast cell invasion

Although mounting evidence suggests a role for [G.sub.12] proteins, [G.sub.α12] and [G.sub.α13], in tumor progression, a direct role of [G.sub.12] proteins has not been determined. This study aims to elucidate the molecular mechanism for a tumorigenic and invasive potential of [G.sub.α12] and [G.sub.α13] in MCF10A human breast epithelial cells. Here, we report, for the first time, that [G.sub.α12] and [G.sub.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.sub.α12/13]. [G.sub.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.sub.α12] and MMP-2 are strongly correlated with the pathogenically diagnosed cancer (P< 0.0001). Moreover, the expression of [G.sub.α12] shows a strong correlation with that of MMP-2 in human breast cancer tissues, implicating the in vivo tumorigenic potential of [G.sub.α12]. Taken together, this study elucidated the role of [G.sub.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.sub.α12] and [G.sub.α13] in breast cell invasion. Keywords [G.sub.α12/13] * Breast cell invasion * MMP-2 * p53