The seeming impairment of retinoid metabolism in human breast tumor cells has been attributed to the lower expression of cellular retinol binding proteins (CRBPs), of alcohol/retinol dehydrogenases, or aldehyde/retinaldehyde dehydrogenases. In a previous study we indicated that xanthine dehydrogenase (XDH) is able to oxidize actively both all-trans-retinol (t-ROL) bound to the CRBP (holo-CRBP) and all-trans-retinaldehyde (t-RAL) to all-trans-retinoic acid (t-RA) in human mammary epithelial cells (HMEC). Since both XDH and CRBP are required for the biosynthesis of t-RA, we have inspected their bioavailability in both estrogen-responsive and nonresponsive human mammary epithelial cancer cells. The XDH activity, as assessed in the crude and purified extracts of both MCF7 and MDA-MB 231 cells by measuring the substrate t-RAL (that unlike t-ROL does not need CRBP), was 6 to 10 times lower than that previously encountered in normal HMEC. In addition, CRBP expression was absent in either cell line. Based on this preliminary evidence, we propose here that the low levels of XDH activity and the associated absence of CRBP in both MCF7 and MDA-MB 231 human breast cancer cells might be responsible for the retinoic acid deficiency observed in these cell model systems. This defect may be the crux of the impairment to stem cell differentiation and, hence, may be primarily implicated in human mammary carcinogenesis.