title: 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.
abstract: 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 liquid chromatography analysis and found a correlation with sensitivity to growth inhibition by RA. RA-sensitive T-47D and MCF-7 cells exhibited high rate metabolism to polar metabolites, whereas RA-resistant MDA-MB-231 and MDA-MB-468 cells metabolized RA to a much lesser extent, and almost no polar metabolites could be detected. The high metabolic rate 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 acid receptor-alpha expression vectors in RA-resistant MDA-MB-231 cells resulted in increased RA metabolism and inhibition of cell proliferation. Metabolism of RA, however, seems not to be required to confer growth inhibition of human breast cancer cells. The biological activity of the polar metabolites formed in RA-sensitive cells was found to be equal or lower than that of RA, indicating that RA itself is the most active retinoid in these cells. Together our data suggest that RA-sensitive cells contain mechanisms to activate strongly the catabolism of RA probably to protect them from the continuous exposure to this active retinoid.
authors.affiliation: Hubrecht Laboratory, Netherlands Institute for Developmental Biology, 3584 CT Utrecht, The Netherlands.
authors.forename: B M
authors.initials: BM
authors.lastname: van der Leede
authors.forename: C E
authors.initials: CE
authors.lastname: van den Brink
authors.forename: W W
authors.initials: WW
authors.lastname: Pijnappel
authors.forename: E
authors.initials: E
authors.lastname: Sonneveld
authors.forename: P T
authors.initials: PT
authors.lastname: van der Saag
authors.forename: B
authors.initials: B
authors.lastname: van der Burg
mesh_terms: D000970:Antineoplastic Agents / Q000378:metabolism / Q000633:toxicity; D001711:Biotransformation; D001943:Breast Neoplasms; D002455:Cell Division / Q000187:drug effects; D016764:Cell Polarity; D002851:Chromatography, High Pressure Liquid; D019008:Drug Resistance, Neoplasm; D005260:Female; D006801:Humans; D014212:Tretinoin / Q000031:analogs & derivatives / Q000378:metabolism* / Q000633:toxicity*; D014407:Tumor Cells, Cultured
chemical_list: D000970:Antineoplastic Agents; C002202:4-oxoretinoic acid; D014212:Tretinoin