Low levels of both xanthine dehydrogenase and cellular retinol binding protein are responsible of the retinoic acid deficiency in malignant human mammary epithelial cells.
Authors: G Taibi, G Carruba, L Cociadiferro, CM Nicotra
Journal: Cancer Research (2009)

Abstract Abstract #4156 The elucidation of the molecular mechanisms underpinning cell differentiation in mammary epithelium is of broad interest and may help understanding the inability of cancer cells to differentiate. In the differentiation of epithelial cells the pivotal role of retinoic acid (RA) was demonstrated early and its deficiency in human mammary cancer cells has been ascribed to the absence of the cellular retinol binding proteins (CRBPs) and the resulting inactivity of the retinol/retinaldehyde dehydrogenase (1,2). We have previously indicated that the enzyme xanthine dehydrogenase (XDH) is able to oxidize actively both all-trans-retinol (t-ROL), bound to the retinol binding protein (CRBP), and all-trans-retinaldehyde (t-RAL) to all-trans-retinoic acid (t-RA) in non-malignant human mammary epithelial cells (HMEC) (3). Since both XDH and CRBP are required for the biosynthesis of t-RA, we have inspected their activity and bioavailability in estrogen-responsive and nonresponsive human mammary epithelial cancer cells. In both MCF7 e MDA-MB 231 mammary tumor cells, retinol oxidation by XDH to RA could not be detected. The XDH activity, as measured in the crude and purified extracts of both cell lines by assaying the substrate t-RAL (that unlike t-ROL does not need CRBP binding) was six to ten times lower than that previously encountered in normal mammary epithelial cells HMEC. In addition, CRBP expression was absent in either cell line. We have also examined the effects of estrogen on both XDH activity and expression in normal and malignant mammary epithelial cells. The exposure of both MCF7 and MDA-MB231 cells to estradiol concentrations ranging from 10 pM up to 100 nM resulted in a marked inhibitory effect on the XDH-driven oxidation of retinaldehyde, with a 34% to 86% reduction with respect to untreated control cell cultures. Furthermore, the XDH protein content, as determined by immunoassay, showed a consistent decrease of 40% with respect to control at 100 nM estradiol. Based on this combined evidence, we propose here that the low levels of XDH activity and the concurrent absence of CRBP in both MCF7 and MDA-MB 231 human breast cancer cells may be responsible for the retinoic acid deficiency observed in these cell model systems. In addition, our data support the concept that estrogen controls negatively retinoic acid bioavailability in mammary tumor cells through the inhibition of XDH enzyme activity and expression. In this context, the impairment of RA biosynthesis may be crucial to disrupt stem cell differentiation and, hence, to promote mammary carcinogenesis and tumor progression.&amp;#x2028; References&amp;#x2028; 1. Kuppumbatti YS, Bleiweiss IJ, Mandeli JP, Waxman S, Mira-y-Lopez R. J Natl Cancer Inst 92:475–480, 2000.&amp;#x2028; 2. Farias EF, Ong DE, Ghyselinck NB, Nakajo S, Kuppumbatti YS, Mira y Lopez R. J Natl Cancer Inst 97:21-29, 2005.&amp;#x2028; 3. Taibi G, Di Gaudio F, Nicotra CMA. J Enz Inhib Med Chem; 23 (3), 2008. Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 4156.