VITAMIN A (RETINOL) AND 4 OXORETINOL IN BREAST CANCER
Principal Investigator: Lorraine Gudas
Abstract: Retinoids, a group of compounds consisting of vitamin A (retinol) and its natural metabolites, have been shown in numerous experimental systems to act as cancer chemopreventive agents and cancer chemotherapeutic agents. While previous research has shown that retinoic acid (RA) is a very potent vitamin A metabolite which causes cell differentiation and inhibition of the growth of tumor cells, we have recently identified two new potent, bioactive vitamin A metabolites, 4-OHretinol and 4-oxoretinol, in a number of cultured tumor cell lines. Although we first isolated these bioactive retinoids, 4- OHretinol and 4-oxoretinol, from a murine cell line (Achkar et al. (1996) PNAS 93:4879-4884), we have recently shown that estrogen receptor (ER) positive cultured human breast cancer cell lines such as MCF-7 can synthesize 4-OHretinol and 4-oxoretinol from retinol under certain culture conditions. In contrast, estrogen receptor negative breast cancer cells do not synthesize 4-OH-retinol and 4-oxoretinol from retinol. We have also recently shown that 4-oxoretinol is growth inhibitory for both ER positive and ER negative breast cancer lines, whereas RA is growth inhibitory in ER positive but not in ER negative breast tumor lines. In this proposal, we want to explore the activity of these new, bioactive retinol metabolites on normal human breast epithelial cells and on breast cancer cells: a) to determine more about the molecular mechanism by which 4-OHretinol and 4-oxoretinol can induce cell growth arrest, and b) to compare 4-oxoretinol with RA with respect to the regulation of gene expression. We will assess whether or not 4- oxoretinol synergizes with RXR specific ligands, N-(4-hydroxyphenyl) retinamide, interferon, TGFbeta, and/or tamoxifen with respect to the growth arrest of breast cancer cells and the regulation of gene expression. We also plan to characterize biochemically the enzyme(s) which converts retinol to 4-OHretinol and 4-oxoretinol, to clone the gene(s) for the enzyme(s), and to delineate its regulation in human breast cancer cells. Tetracycline inducible antisense RNA techniques will be employed to block the expression of this gene. Our proposed studies may lead to the use of 4-oxoretinol or related compounds in the prevention and/or treatment of human breast cancer.
Funding Period: 1998-04-01 - 2004-01-31
more information: NIH RePORT
- Valproic acid, in combination with all-trans retinoic acid and 5-aza-2'-deoxycytidine, restores expression of silenced RARbeta2 in breast cancer cellsNigel P Mongan
Department of Pharmacology, Weill Medical College, Cornell University, 1300 York Avenue, New York, NY 10021, USA
Mol Cancer Ther 4:477-86. 2005..These data suggest that VPA may ultimately be useful in combination therapies in the treatment of human breast cancers...
- Metabolism and regulation of gene expression by 4-oxoretinol versus all-trans retinoic acid in normal human mammary epithelial cellsLimin Liu
Department of Pharmacology, Weill Cornell Medical College of Cornell University, New York, New York 10065, USA
J Cell Physiol 220:771-9. 2009....