Vitamin A metabolism is impaired in human ovarian cancer.
OBJECTIVE
We have previously reported that loss in expression of a protein considered critical for vitamin A homeostasis, cellular retinol-binding protein 1 (CRBP1), is an early event in ovarian carcinogenesis. The aim of the present study was to determine if loss of vitamin A metabolism also occurs early in ovarian oncogenesis.


METHODS
We assessed CRBP1 expression by immunohistochemistry in ovaries prophylactically removed from women with a genetic risk for ovarian cancer. Furthermore, we investigated the ability of normal, immortalized but nontumorigenic, and tumorigenic human ovarian epithelial cells to synthesize retinoic acid and retinaldehyde when challenged with a physiological dose of retinol, and determined expression levels of the retinoid-related genes, RARalpha, RXRalpha, CRABP1, CRABP2, RALDH1 and RALDH2 in these cells.


RESULTS
Immunohistochemistry revealed loss of CRBP1 expression in potentially preneoplastic lesions in prophylactic oophorectomies. HPLC analysis of vitamin A metabolism showed production of retinoic acid in four independent, normal human ovarian surface epithelial (HOSE) cell cultures upon exposure to retinol. However, only one of two SV40-immortalized HOSE cell lines made RA, while none of the ovarian carcinoma cell lines produced detectable RA due to complete loss of RALDH2.


CONCLUSIONS
The impaired conversion of retinol to RA in ovarian cancer cells and decreased CRBP1 protein expression in prophylactic oophorectomies support our hypothesis that concomitant losses of vitamin A metabolism and CRBP1 expression contribute to ovarian oncogenesis.
Williams
Stephen J
SJ
Ovarian Cancer Program, Department of Medical Oncology, Fox Chase Cancer Center, 333 Cottman Avenue W310, Philadelphia, PA 19111, USA. SJ_Williams@fccc.edu
Cvetkovic
Dusica
D
Hamilton
Thomas C
TC
D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007150:Immunohistochemistry; D010051:Ovarian Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D010084:Oxidation-Reduction; D012172:Retinaldehyde / Q000378:metabolism; D054840:Retinol-Binding Proteins, Cellular / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism; D014212:Tretinoin / Q000378:metabolism / Q000494:pharmacology; D014801:Vitamin A / Q000378:metabolism*
D054840:Retinol-Binding Proteins, Cellular; D014801:Vitamin A; D014212:Tretinoin; D012172:Retinaldehyde