EFFECT OF 9-CIS-RETINOIC ACID ON GROWTH AND RXR EXPRESSION IN HUMAN BREAST-CANCER CELLS

A number of studies have demonstrated the ability of retinoic acid (RA ) to inhibit the growth of estrogen receptor-positive (ER(+)) human br east cancer cell lines. The precise mechanism of growth inhibition is not known. However, the biological effects of RA in other model system s have been shown to be mediated via the nuclear retinoic acid recepto rs (RARs) and the retinoid X receptors (RXRs). While several laborator ies have examined the expression of RARs in various breast cancer cell lines, no information is available concerning the role of the RXRs an d 9-cis-RA, the natural ligand of RXRs, in the response of breast canc er cells to RA. Using a representative panel of breast cancer cell lin es, we determined the effect of 9-cis-RA on growth and cell cycle stag e distribution, analyzed steady-state mRNA levels of RXR-alpha, -beta, and -gamma, and determined the effect of all-trans-RA and 9-cis-RA on RXR expression. Our results show that: (1) the growth of ER(+)/RA-sen sitive breast cancer cells is inhibited by treatment with 9-cis-RA by blocking entry into S phase; (2) both ER(+)/RA-sensitive and ER(-)/RA- resistant breast cancer cell lines express RXR-alpha and RXR-beta mRNA s but not RXR-gamma; however, levels of these transcripts did not corr elate with the RA response; and (3) levels of RXR-alpha and RXR-beta m RNA were not significantly altered following treatment with either all -trans-HA or 9-cis-RA. These results suggest that the mechanism respon sible for the retinoid sensitivity of breast cancer cells does not inv olve transcriptional modulation of the RXRs by RA. (C) 1995 Academic P ress, Inc.