Retinoids and
gamma-interferon (IFN-gamma) have been demonstrated to synergistically amplify growth inhibition in cultured
breast cancer cells. Since IFN-gamma enhances effects mediated by
retinoids more than vice versa, we focused our investigations on the
mRNA expression of cellular
retinoic acid-binding proteins (CRABPs) and
retinoic acid receptors (RARs), since these are the key molecules that mediate
retinoid action. Synergistic inhibition of cell proliferation under treatment with
9-cis-retinoic acid and IFN-gamma was detected in the three
breast cancer cell lines MCF-7, SKBR-3, and even in the RA-resistant BT-20 cells. RAR-alpha and
RAR-gamma mRNA were observed in all cell lines, whereas
RAR-beta was not detectable.
CRABP I message was expressed in MCF-7 cells only, but
CRABP II was found in all three
breast cancer cell lines. IFN-gamma (10 ng/ml) increased
RAR-gamma expression but had no influence on RAR-alpha, whereas
RAR-beta was not detectable in any of the cell lines. RA (1 microM)-mediated
CRABP II increase was suppressed by IFN-gamma (10 ng/ml). These observations indicate that IFN-gamma-mediated increase in
RAR-gamma and suppression of RA-mediated
CRABP II activation may play a role in synergistic inhibition of proliferation in
breast cancer cell lines.