AUTOINDUCTION OF RETINOIC ACID METABOLISM TO POLAR DERIVATIVES WITH DECREASED BIOLOGICAL-ACTIVITY IN RETINOIC ACID-SENSITIVE, BUT NOT IN RETINOIC ACID-RESISTANT HUMAN BREAST-CANCER CELLS

Previous studies have shown that all-trans-retinoic acid (RA) inhibits in vitro proliferation of hormone-dependent human breast cancer cells but not the growth of hormone-independent cells, Here we report on RA metabolism in breast cancer cells as examined by high performance liq uid chromatography analysis and found a correlation with sensitivity t o growth inhibition by RA, RA-sensitive T-47D and MCF-7 cells exhibite d high rate metabolism to polar metabolites, whereas RA-resistant MDA- MB 231 and MDA-MB-468 cells metabolized RA to a much lesser extent, an d almost no polar metabolites could be detected. The high metabolic ra te in RA-sensitive cells appears to be the result of autoinduction of RA metabolism, whereas RA-resistant cells showed no such induction of metabolism, We observed furthermore that transfection with retinoic ac id receptor-alpha expression vectors in RA-resistant MDA-MB-231 cells resulted in increased RA metabolism and inhibition of cell proliferati on, Metabolism of RA, however, seems not to be required to confer grow th inhibition of human breast cancer cells, The biological activity of the polar metabolites formed in RA-sensitive cells was found to be eq ual or lower than that of RA, indicating that RA itself is the most ac tive retinoid in these cells, Together our data suggest that RA-sensit ive cells contain mechanisms to activate strongly the catabolism of RA probably to protect them from the continuous exposure to this active retinoid.