RETINOIC ACID RECEPTOR ALPHA-1 ISOFORM IS INDUCED BY ESTRADIOL AND CONFERS RETINOIC ACID SENSITIVITY IN HUMAN BREAST-CANCER CELLS

Retinoic acid (RA) inhibits proliferation of estrogen receptor (ER)-po sitive human breast cancer cells, but not the growth of ER-negative ce lls. We have shown previously that ER-positive cells express higher le vels of retinoic acid receptor (RAR) alpha, suggesting that RAR alpha gene expression may be regulated in breast cancer cells by estrogens. We here report that estradiol (E2) increases RAR alpha mRNA in a time- and concentration-dependent manner resulting in a marked increase in RAR alpha protein expression, and present evidence that RAR alpha 1 is the only known isoform of RAR alpha regulated by E2 in breast cancer cells. In parallel we demonstrate that ER-positive cells exhibit great er RA sensitivity in the presence of E2, suggesting that E2-induced ex pression of RAR alpha 1 is involved in growth inhibition by RA. To dir ectly investigate the role of RAR alpha 1 in RA-mediated growth inhibi tion, we introduced RAR alpha 1 expression vectors into RA-resistant a nd ER-negative MDA-MB-231 cells. The RAR alpha 1-transfected cells wer e growth inhibited by RA, while mock- and untransfected cells were unr esponsive. Together, our data indicate that adequate levels of RAR alp ha 1, either generated by introduction of expression vectors or endoge nously induced by estrogens, are required for growth inhibition of bre ast cancer cells by RA.