Cellular retinol-binding protein expression and breast cancer

Background: The biologic activity of vitamin A depends, in part, on its met abolism to active nuclear receptor ligands, chiefly retinoic acid. The cell ular retinol-binding protein (CRBP) binds vitamin A with high affinity and is postulated to regulate its uptake and metabolism. In this report, we ana lyze the expression of CRBP in normal and malignant breast tissues. Methods : We evaluated CRBP expression by in situ hybridization in six reduction ma mmoplasty specimens and 49 human breast carcinoma specimens by use of digox igenin-labeled RNA probes and in nine cultured mammoplasty specimens by nor thern or western blot analysis. Statistical significance was evaluated with the chi(2) test or Fisher's exact test if the sample sizes were small, All P values are from two-sided tests. Results: CRBP was expressed in all 15 m ammoplasty specimens (normal breast tissue) and in 33 of 35 available speci mens of normal tissue adjacent to carcinoma. In contrast, 12 (24%) of 49 ca rcinoma lesions were uniformly negative for CRBP (P = .023 for comparison w ith adjacent normal breast tissue), The loss of CRBP expression was as freq uent in ductal carcinoma in situ (six [27%] of 22) as in invasive lesions ( six [22%] of 27), suggesting that it is a relatively early event in carcino genesis and not associated with patient age, tumor grade, and expression of steroid receptors or c-Myc, Preliminary experiments did not find an associ ation between CRBP and retinoic acid receptor beta loss, but most (four of five) CRBP-negative tumors were also retinoic acid receptor beta negative. Conclusion: CRBP is underexpressed in 24% (95% confidence interval 12.5%-36 .5%) of human breast carcinomas, implying a link between cellular vitamin A homeostasis and breast can-cer. We hypothesize that the loss of CRBP restr icts the effects of endogenous vitamin A on breast epithelial cells.