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

Retinoic acid activation of retinoic acid receptor alpha (RAR alpha) induce s protein kinase C alpha (PKC alpha) expression and inhibits proliferation of the hormone-dependent T-47D breast cancer cell line. Retinoic acid has n o 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 ret inoic acid-induced growth arrest of human breast cancer cells we establishe d MDA-MB-231 cell lines stably expressing PKC alpha. Constitutive expressio n of PKC alpha did not affect proliferation of MDA-MB-231 cells but did res ult in partial retinoic acid sensitivity. Retinoic acid treatment of PKC al pha -MDA-MB-231 cells decreased proliferation (by similar to 40%) and inhib ited serum activation of MAP kinases and induction of c-fos. Similar result s were seen in MDA-MB-231 cells in which transcription of the transfected P KC alpha cDNA was reversibly induced by isopropyl beta -D-thiogalactoside. Expression of RAR alpha in PKC alpha expressing MDA-MB-231 cells resulted i n even greater retinoic acid responses, as measured by effects on cell prol iferation, inhibition of serum signaling, and transactivation of an RARE-CA T reporter plasmid. In summary, PKC alpha synergizes with activated RAR alp ha to disrupt serum growth factor signaling, ultimately arresting prolifera tion of MDA-MB-231 cells. (C) 2001 Academic Press.