Defects in vitamin A, or retinol, bioactivity may be a possible contributor to human carcinogenesis because vitamin A is required for activation of the retinoic acid receptor (RAR), which induces differentiation of adult epithelial cells. One of the characteristics of epithelial cancers is the loss of differentiated attributes. It has been hypothesized that vitamin A bioactivity in cancer cells may be compromised at the level of retinol metabolism, which is regulated by a number of proteins, including cellular retinol-binding protein I (CRBP-I). A study of CRBP-I in mice demonstrated that the protein plays an essential role in vitamin A storage. In addition, CRBP-I expression is down-regulated in about a quarter of human breast cancers. However, it is not known if reduced CRBP-I function compromises vitamin A bioactivity and, if so, whether such a reduction in function would lead to a loss of differentiation and tumor progression.
To determine whether there is a link between retinol storage, RAR activation, and CRBP-I function in the development of breast cancer, Eduardo F. Farias, Ph.D., of Mount Sinai School of Medicine in New York, and colleagues studied RAR activity, retinol storage, CRBP-I localization, and cell differentiation in human and mouse mammary epithelial cells--which can be used as a model of breast cancer--that expressed normal or mutant CRBP-I.
They found that, in the cells, RAR activation was dependent on CRBP-I-mediated retinol storage, and downregulation of CRBP-I compromised RAR activity, leading to loss of cell differentiation and tumor progression. The authors also observed that the breast tumors derived from these cells that expressed normal CRBP-I regressed, whereas those that did not express CRBP-I continued to grow.
"Our in vivo data suggest that somatic CRBP-I loss of function results in a local deficit in vitamin A storage and metabolism that has profound consequences for the affected tissue, despite presumably normal circulating levels of vitamin A," the authors write. "The consequence of deficient vitamin A storage is a fundamental point that needs to be studied further, but if CRBP-I is indeed essential…, then epidemiologic studies attempting to correlate human vitamin A status with cancer incidence may have been partly misguided."
In an editorial, Reuben Lotan, M.D., of the University of Texas M. D. Anderson Cancer Center in Houston, discusses the role of retinoids in normal development and suggests future research strategies to determine how retinoids may prevent tumor formation and growth of both hormone receptor–positive and –negative breast cancers.
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JNCI Journal of the National Cancer Institute