No abstract

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.

Mounting evidence suggests a role for the G12 proteins, Gα12 and Gα13, in the metastatic tumor progression. A direct role of G12 proteins in malignant phenotypic changes, however, has not been determined. This study aims to elucidate the molecular mechanism for a metastatic potential of Gα12 and Gα13 in MCF10A human breast epithelial cells using GTPase‐deficient active Gα12 (Gα12QL) and Gα13 (Gα13QL). Here we report, for the first time, that Gα12/13 induce upregulation of matrix metalloproteinase (MMP)‐2, leading to the invasive/migratory phenotypes in MCF10A cells while MMP‐9 is affected by neither Gα12QL nor Gα13QL. We further show that p53 is an important transcription factor for induction of MMP‐2 transcriptional activation by Gα12 and Gα13. MKK3/6, p38 MAPK and Akt were required for the Gα12/13‐induced MMP‐2 upregulation, invasion and migration of MCF10A cells. Taken together, this study elucidated a role of Gα12/13 in regulating process for MMP‐2 expression and malignant phenotypic conversion of MCF10A human breast epithelial cells, providing a molecular basis for the promoting role of Gα12 and Gα13 in breast cell invasion. [Supported by the KOSEF grant (MEST, No. R11‐2007‐107‐01002‐0), and by the KOSEF NRL Program grant funded by the Korea government (MEST, No. ROA‐2008‐000‐20070‐0).]