Protein kinase Cα expression confers retinoic acid sensitivity on MDA-MB-231 human breast cancer cells

Retinoic acid activation of retinoic acid receptor alpha (RAR alpha) induces protein kinase C alpha (PKC alpha) expression and inhibits proliferation of the hormone-dependent T-47D breast cancer cell line. Retinoic acid has no effect on proliferation or PKC alpha expression in a hormone-independent, breast cancer cell line (MDA-MB-231). To test the role of PKC alpha in retinoic acid-induced growth arrest of human breast cancer cells we established MDA-MB-231 cell lines stably expressing PKC alpha. Constitutive expression of PKC alpha did not affect proliferation of MDA-MB-231 cells but did result in partial retinoic acid sensitivity. Retinoic acid treatment of PKC alpha -MDA-MB-231 cells decreased proliferation (by similar to 40%) and inhibited serum activation of MAP kinases and induction of c-fos. Similar results were seen in MDA-MB-231 cells in which transcription of the transfected PKC alpha cDNA was reversibly induced by isopropyl beta -D-thiogalactoside. Expression of RAR alpha in PKC alpha expressing MDA-MB-231 cells resulted in even greater retinoic acid responses, as measured by effects on cell proliferation, inhibition of serum signaling, and transactivation of an RARE-CAT reporter plasmid. In summary, PKC alpha synergizes with activated RAR alpha to disrupt serum growth factor signaling, ultimately arresting proliferation of MDA-MB-231 cells. (C) 2001 Academic Press.