title: Retinol conversion to retinoic acid is impaired in breast cancer cell lines relative to normal cells.
abstract: The bioactivity of retinol (vitamin A) is in part dependent on its metabolism to retinoic acid (RA). We investigated the ability of breast epithelial cells to synthesize RA when challenged with a physiological retinol dose (2 microM). Normal human mammary epithelial cells (HMEC) cultured from reduction mammoplasties were competent in RA synthesis and the ability to synthesize RA was retained by immortal, nontumorigenic breast epithelial cell lines (MTSV1.7, MCF-10F, and 184B5). In contrast, most (five of six) breast cancer cell lines could not synthesize RA or did so at low rates relative to normal cells. A notable exception was the MDA-MB-468 cell line, which was fully competent in RA synthesis. Most (>/=68%) of the RA synthesized by breast cells was recovered from the culture medium. Cellular retinol binding protein and cellular RA binding protein II, both expressed in HMEC, had various expression patterns in the cell lines that did not correlate with the observed differences in RA synthesizing ability. Strong RA induction of the RA hydroxylase P450RAI (CYP26) was confined to ERalpha-positive T47D and MCF-7 breast cancer cells and did not appear to explain the lack of detectable RA levels in these cells since RA remained undetectable when the cells were treated with 5-10 microM liarozole, a P450RAI inhibitor. We hypothesize that retinol bioactivity is impaired in breast cancer cells that cannot synthesize RA. In preliminary support of this hypothesis, we found that retinol (0.5-2 microM) inhibited MCF-10F but not T47D or MCF-7 cell growth.
authors.affiliation: Department of Medicine, Mount Sinai School of Medicine, New York, New York, USA. mira@msvax.mssm.edu
authors.forename: R
authors.initials: R
authors.lastname: Mira-Y-Lopez
authors.forename: W L
authors.initials: WL
authors.lastname: Zheng
authors.forename: Y S
authors.initials: YS
authors.lastname: Kuppumbatti
authors.forename: B
authors.initials: B
authors.lastname: Rexer
authors.forename: Y
authors.initials: Y
authors.lastname: Jing
authors.forename: D E
authors.initials: DE
authors.lastname: Ong
mesh_terms: D001940:Breast / Q000166:cytology / Q000378:metabolism; D001943:Breast Neoplasms / Q000378:metabolism* / Q000473:pathology; D002352:Carrier Proteins / Q000378:metabolism; D002461:Cell Line, Transformed; D002478:Cells, Cultured; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D005260:Female; D006801:Humans; D006899:Mixed Function Oxygenases / Q000378:metabolism; D012016:Reference Values; D000072516:Retinoic Acid 4-Hydroxylase; D014212:Tretinoin / Q000378:metabolism*; D014801:Vitamin A / Q000378:metabolism*
chemical_list: D002352:Carrier Proteins; D014801:Vitamin A; D014212:Tretinoin; D003577:Cytochrome P-450 Enzyme System; D006899:Mixed Function Oxygenases; D000072516:Retinoic Acid 4-Hydroxylase