RETINOID-RESISTANT ESTROGEN RECEPTOR-NEGATIVE HUMAN BREAST-CARCINOMA CELLS TRANSFECTED WITH RETINOIC ACID RECEPTOR-ALPHA ACQUIRE SENSITIVITY TO GROWTH-INHIBITION BY RETINOIDS

Retinoids mediate their actions via RARs (retinoic acid receptors) and RXRs (retinoid X receptors). Each class of these nuclear retinoid rec eptors is further subdivided into three species, namely alpha, beta, a nd gamma. Recent studies demonstrate that estrogen receptor (ER)-posit ive human breast carcinoma (HBC) cell lines and tumor samples exhibit significantly higher levels of RAR alpha than their ER-negative counte rparts. ER-positive HBC cell lines are sensitive to, and ER-negative c ell Lines are resistant to, growth inhibitory effects of retinoic acid (RA). We previously demonstrated that the expression of functional ER s in an established ER-negative cell line resulted in higher levels of RAR alpha and sensitivity to growth inhibition by RA. To further inve stigate the major role of RAR alpha in retinoid-mediated inhibition of growth, we transfected RAR alpha cDNA in two RA-resistant ER-negative HBC cell lines. Analyses of different clonal populations of RAR alpha transfectants from each cell line revealed growth inhibition by retin oids. Utilizing RAR- and RXR-class selective retinoids, we further dem onstrated that only the RAR alpha-selective retinoids mediated the gro wth inhibition in these cells, while the RXR-selective retinoids were biologically inert. We thus provide evidence that the molecular mechan isms of retinoid inhibition of HBC proliferation predominantly involve RAR alpha.