Breast cancer incidence has steadily increased over the last three decades such that the disease is now the most common malignancy among women. Observational and interventional studies in humans, support an association between vitamin A supplementation and a reduced risk for breast cancer. In animal models, vitamin A deficiency results in an increased susceptibility to epithelial cancers, while supplementation with vitamin A or specific analogs (retinoids) decreases the incidence and number of carcinogen-induced mammary tumors. The mechanism by which these retinoids exhibit their anti-cancer effects is unknown. The vitamin A metabolite retinoic acid (RA) is now known to mediate much of the biological activity of vitamin A by directly modulating gene expression. Endogenous RA, synthesized in situ, is responsible for maintaining the differentiated state of epithelial cells. Breast cancer cells respond to RA by reductions in estrogen or growth factor-stimulated cell proliferation, reductions in invasive or tumorigenic properties, and increased expression of genes associated with a more differentiated phenotype. Recent evidence indicates that vitamin A metabolism may be altered in cancerous tissues and that the resulting functional reductions in RA may be a causative factor in progress of the disease. There is, however, a paucity of information concerning how breast cancer cells regulate levels of RA. We suggest that breast cancer cells may exhibit a phenotype rendering them incapable of the metabolic generation and/or maintenance of RA at levels necessary to control differentiation and proliferation. The experiments presented in this proposal are designed to address this hypothesis. Using normal breast tissue and tumor specimens as well as normal human mammary epithelial cells and established mammary carcinoma cell lines, the objectives of the experiments in this proposal are to: 1) establish whether there are differences in RA synthetic or catabolic activity between normal breast epithelial cells and breast tumors or representative breast cancer cell lines; 2) establish whether there are differences in the expression pattern of genes encoding enzymes or binding proteins involved in RA metabolism; 3) determine whether altering RA metabolism via genetic manipulation results in changes in the neoplastic and tumorigenic properties of breast cancer cells. Given the link between retinoid modulation of gene expression (including those implicated in cancer progression) and the fact that proteins involved in metabolism and the RA signalling pathway are retinoid responsive, elucidating the role of retinoid metabolism breast cancer cells will be a key to understanding the role of vitamin A in carcinogenesis.
| Hayden, Leslie J; Satre, Michael A (2002) Alterations in cellular retinol metabolism contribute to differential retinoid responsiveness in normal human mammary epithelial cells versus breast cancer cells. Breast Cancer Res Treat 72:95-105 |
| Hayden, L J; Hawk, S N; Sih, T R et al. (2001) Metabolic conversion of retinol to retinoic acid mediates the biological responsiveness of human mammary epithelial cells to retinol. J Cell Physiol 186:437-47 |
| Jessen, K A; Satre, M A (2000) Mouse retinol binding protein gene: cloning, expression and regulation by retinoic acid. Mol Cell Biochem 211:85-94 |
