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Epigenetic Basis of Vitamin A Resistance in Breast Cancer. Implications for Prevention and Treatment.

Authors :
Pozzi, Silvia
Ren, Mingqiang
Somenzi, Giulia
Bistulfi, Gaia
Ghidoni, Riccardo
Sirchia, Silvia M.
Sacchi, Nicoletta
Source :
Journal of Nutrition; Nov2003 Supplement 1, Vol. 133 Issue 11, p3852S-3852S, 1/2p
Publication Year :
2003

Abstract

Understanding the relationship between genes and diet may improve cancer prevention and treatment. Genes and genomes seem able to adapt to dietary cues by epigenetic changes via postsynthetic modifications of either the DNA itself or the histone proteins that are intimately associated with DNA. We are beginning to understand the relationship among diet, individual gene differences (polymorphisms), and epigenetic modulation of genes and genomes and the direct influence of diet on the epigenetic status of genes and genomes. Vitamin A and its natural bioactive derivative retinoic acid (RA) have received a lot of attention for their potential anticancer effects on epithelial cells. However, in vitro studies and clinical trials using RA as a differentiation agent have shown that cancer cells are refractory to RA. RA action is normally mediated by retinoid receptors (RARs and RXR). RARs are transcriptionally active in the presence of both RA and activator-coactivator complexes with histone acetyltransferase activity. In contrast, they are repressed in the absence of RA by corepressor complexes with histone deacetylase activity. We found that RAR-beta is methylated in breast cancer cell lines and tumors (1) and that breast cancer patients with RAR-beta-methylated tumors do not respond to RA differentiation therapy (2). Recently, we found that RAR-beta methylation is present in normal epithelial cells adjacent to tumor cells in breast tissue, suggesting that epigenetic modifications leading to epigenetic RA resistance are likely an early event in the process of breast tumorigenesis. We hypothesized that factors leading to RAR-beta inactivity in human breast epithelial cells may predispose them to development of epigenetic RA resistance. When we forced RARbeta into transcriptional inactivity, we observed the appearance of epigenetic modifications at RAR-beta (DNA methylation, histone modifications) leading to RA resistance in breast epithelial cells. Our studies suggest that we may prevent the development of RA resistance in breast epithelial cells by preventing transcriptional inactivation of vitamin A signaling. Moreover, our studies show that we can reverse epigenetic changes leading to RA resistance and restore RA sensitivity in breast cancer cells. These studies may have a general validity for prevention and treatment of breast cancer as well as other epithelial cancers where we also observed the molecular signatures of epigenetic RA resistance. [ABSTRACT FROM AUTHOR]

Details

Language :
English
ISSN :
00223166
Volume :
133
Issue :
11
Database :
Complementary Index
Journal :
Journal of Nutrition
Publication Type :
Academic Journal
Accession number :
11574223