Signaling and Regulation Lysophosphatidic Acid–Induced p21 Expression Mediates the Cytostatic Response of Breast and Ovarian Cancer Cells to TGFb

Lysophosphatidic acid (LPA) is a multifunctional intercellular phospholipid mediator present in blood and other biological fluids. In cancer cells, LPA stimulates expression or activity of inflammatory cytokines, angiogenic factors, matrixmetalloproteinases, and other oncogenic proteins. In this study, we showed that LPA upregulated expression of the cyclin-dependent kinase inhibitor p21 in TGFb-sensitive breast and ovarian cancer cells, but not in TGFb-resistant ones. We examined the possibility that LPA-induced p21 might contribute to the cytostatic response to TGFb. In serum-free conditions, TGFb alone induced p21 expression weakly in TGFb-sensitive cells. Serum or serum-borne LPA cooperated with TGFb to elicit the maximal p21 induction. LPA stimulated p21 via LPA1 and LPA2 receptors and Erk-dependent activation of the CCAAT/enhancer binding protein beta transcription factor independent of p53. Loss or gain of p21 expression led to a shift between TGFb-sensitive and -resistant phenotypes in breast and ovarian cancer cells, indicating that p21 is a key determinant of the growth inhibitory activity of TGFb. Our results reveal a novel cross-talk between LPA and TGFb that underlies TGFb-sensitive and -resistant phenotypes of breast and ovarian cancer cells. Mol Cancer Res; 9(11); 1562–70. 2011 AACR.