EFFECTS OF ALL-TRANS-RETINOIC ACID AND 13-CIS-RETINOIC ACID ON BREAST-CANCER CELL-LINES - GROWTH-INHIBITION AND APOPTOSIS INDUCTION

Interest has been increasingly focused on all-trans-retinoic acid (tRA ) and 13-cis-retinoic acid (13cRA) in cancer chemoprevention and treat ment. We have examined the in vitro effects of these 2 retinoic acids (RAs) on human breast-cancer cell lines MCF-7 and ZR-75.1 (both estrog en-receptor-positive, ER(+)) and MDA-MB-231 (estrogen-receptor-negativ e, ER(-)), in terms of inhibition of proliferation and induction of ap optosis. Both retinoic acids exerted an evident dose-dependent growth inhibition, although in the ER(-) cell line the anti-proliferative eff ect was obtained only with the highest concentration used; the anti-pr oliferative activity of tRA was more evident than 13cRA on all 3 teste d cell lines. tRA and 13cRA induced apoptosis in MCF-7 and MDA-MB-231 cell lines, but not in ZR-75.1. The apoptotic phenomenon was clearly t ime-dependent, and in our experience it was not related to the arrest in a specific phase of cell cycle. After treatment with RAs the levels of bcl-2 were reduced in MCF-7, while in ZR-75.1 and in MDA-MB-231 no treatment-related modifications were observed. An analysis of estroge n-receptor status, used as a marker of differentiation, demonstrated t hat after treatment with RAs the levels of estrogen receptor (ER) decr eased in ZR-75.1 only. Our study indicates that the anti proliferative effects of RAs are sustained by induction of apoptosis in MCF-7 and M DA-MB-231 cells, while in ZR-75.1 cells an induction of differentiatio n without apoptosis was the prevalent mechanism of growth inhibition. Our results encourage further studies on in vivo effects of these reti noids in breast cancer. (C) 1997 Wiley-Liss, Inc.