Retinoic Acid Biosynthesis Is Inhibited By Estrogen

The striking influence of retinoic acid on differentiation of epithelial cells and its efficacy to suppress cell proliferation (1,2) prompted studies aimed to clarify its molecular mechanisms and its homeostasis in normal and malignant cells. Several dehydrogenases are involved in the conversion of retinol to retinoic acid. Furthermore, retinoic acid deficiency has been demonstrated in tumor epithelial cells and ascribed to the lack of cellular retinol binding protein (CRBP) and/or to the inactivity of retinol/retinaldehyde dehydrogenase enzyme system (3,4). Our studies on the biosynthesis of retinoic acid in normal mammary epithelial cells (HMEC) have revealed the crucial role of the xanthine dehydrogenase (XDH) enzyme in the conversion of retinol/retinaldehyde to retinoic acid and the necessary participation of CRBP in this process. In MCF7 and MDA-MB231 cells, both lacking CRBP, retinol oxidation to retinoic acid by XDH could not be observed. However, XDH catalyzes retinaldehyde conversion to retinoic acid, albeit less actively than in HMEC (5). Estrogens affected both XDH expression and activity in both normal and tumor mammary epithelial cells. Estradiol, added to MCF7 and MDA-MB231 cell cultures at concentrations varying from 10 pM to 100 nM, exerted in fact a marked inhibitory effect on the XDH-driven retinaldehyde oxidation, with the enzyme activity dropping to 14-66% of that observed in control cell cultures. The XDH protein content was also reduced to 40% by 100 nM estradiol. This evidence suggests that estrogens have a profound negative on retinol-retinoic acid homeostasis and consequently are primary regulators of cell differentiation.