Although mounting evidence suggests a role for G12 proteins, Gα12 and Gα13, in tumor progression, a direct role of G12 proteins has not been determined. This study aims to elucidate the molecular mechanism for tumorigenic/invasive potential of Gα12/13 in MCF10A human breast epithelial cells. 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. We further show that p53 is an important transcription factor for induction of MMP‐2 transcriptional activation by Gα12/13. Using human breast tissue samples, we demonstrate that the expression levels of Gα12 and MMP‐2 are strongly correlated with the pathogenically diagnosed cancer. To elucidate a causal relationship between inflammation and the control of invasiveness of breast cells, the effect of the inflammatory lipid sphingosine‐1‐phosphate(S1P) on the regulation of invasive/migratory phenotypes of MCF10A cells was investigated. S1P causes induction of MMP‐9 in vitro/in vivo, and enhances invasion/migration which is triggered by S1P3‐Gαq coupling. Activation of PLC‐β4 and intracellular Ca2+ release are required for S1P‐induced MMP‐9 upregulation. Taken together, this study elucidated the role of G12 proteins and S1P in regulating processes for MMP expression and malignant phenotypic conversion of breast cells.

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