Role of PKC in Retinoic Acid Regulation of Human Mammary Cancer CellProliferation

摘要

The data presented in this first annual report (for award DAMD17-96-1-6022)support our hypothesis for a mechanism of retinoic acid induced growth arrest of human breast cancer cells. Specifically we believe that retinoic acid induced growth arrest of human breast cancer cells requires protein kinase C alpha expression and activity. The inhibition of uncontrolled proliferation following retinoic acid treatment of hormone dependent, TA7D breast cancer cell lines, was consistent with retinoic acid inducing expression of PKC alpha and concomitant repression of PKC alpha expression. The changes in PKC alpha and PKC zeta reflected retinoic acid induced changes in mRNA. In contrast, retinoic acid had no effect on growth or PKC expression in hormone independent, MDA-MB-231 breast cancer cells. RAR alpha-selective synthetic retinoid, Am58O, was equally effective as retinoic acid at growth arrest and the induction of PKC alpha, but not reduction in PKC zeta of T-47D cells. Addition of Go6976, a selective inhibitor of conventional PKC, prevented the Am58O induced reduction in proliferation. In total, our interpretation is that retinoic acid arrests proliferation of T-47D cells following RARa dependent induction, and activation of PKC alpha. By manipulating the expression of PKC alpha, we also have shown that expression of PKC alpha is sufficient to exert growth inhibitory effects on T-47D cells.