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Epigenetic Silencing of BRCA-1 and Protective Effects of Dietary Components
Tumor Cell Biology VI
Background. The expression of the tumor suppressor gene BRCA-1 is reduced in a large percentage of sporadic breast tumors suggesting that silencing of the BRCA-1 gene through epigenetic mechanisms may contribute to the onset of sporadic breast cancer. Diet is an important vehicle of exposure to dioxins, of which TCDD is a prototype ligand of the aromatic hydrocarbon receptor (AhR). Our objective is to understand how dioxins lead to epigenetic silencing of BRCA-1 and determine whether this abnormal regulation can be reversed with dietary compounds. Studies revealed that TCDD induced the recruitment of the activated AhR to the BRCA-1 promoter. This was paralleled by reduced occupancy at the BRCA-1 gene of histone acetyltransferases (HATs) and the increased recruitment of histone deacetylases (HDACs). The removal of acetyl groups from histones along with other histone modifications may result in DNA methylation, the formation of heterochromatin, and silencing of the BRCA-1 gene. Selected dietary compounds may exert protective effects against dioxins by blocking the recruitment of the AhR to the BRCA-1 promoter, inhibiting AhR-induced DNA methylation, or preventing specific dioxin-induced histone modifications. Hypothesis: epigenetic silencing of the BRCA-1 gene by dioxins might be reversed by natural dietary agents. Specific Aims. Specific Aim 1 will examine in normal and breast cancer cells whether TCDD-dependent changes in BRCA-1 transcription and promoter occupancy might be reversed by dietary modulators of the AhR; Specific Aim 2 will examine whether TCDD induces DNA methylation and nucleosome remodeling of the BRCA-1 gene and determine if these effects can be reversed by dietary DNA methyltransferase inhibitors. Specific Aim 3 will investigate the histone modifications induced at the BRCA-1 promoter by TCDD and whether these changes can be reversed by dietary HDAC inhibitors. Methodology. These studies will be conducted in normal primary epithelial and breast cancer cells. Potential outcomes of this project are an understanding of the chromatin remodeling events induced by dioxins that lead to transcriptional repression of BRCA-1 and the development of preventative dietary strategies.
Background. Sporadic breast cancers represent 90-95% of breast cancer cases, whereas only 5-10% of breast tumors are linked to family history. In order to eradicate breast cancer, it is imperative to determine whether and how environmental insults contribute to the etiology of sporadic breast tumors. Understanding of sporadic breast cancers will only be achieved once we have defined the environmental agents and molecular targets involved. Dioxins are environmental factors, which have been found in human breast tissue and milk. The exposure to dioxins appears to be causally related to reduced expression of the tumor suppressor gene, BRCA-1, an important component of the DNA repair system. Our immediate objectives are 1) to define the mechanisms for the dioxin-related repression of BRCA-1 expression, and 2) to test if some of these mechanisms might be reversed by natural dietary agents. Hypothesis: Since dioxins silence the BRCA-1 gene in breast epithelial cells, this repression may be reversed by natural dietary agents. Specific Aims are designed to determine the molecular components of BRCA-1 repression by dioxins and the protective efficacy of selected natural dietary phytochemicals. The study design includes comparisons of regulation of BRCA-1 expression by dioxins and dietary agents in normal primary mammary epithelial cells and breast cancer cells. The methodology includes a series of molecular approaches to study histone and DNA modifications associated with the BRCA-1 gene. Potential outcomes and benefits of the research include an understanding of the mechanisms of BRCA-1 repression by dioxins and the development of dietary models that may retard and possibly prevent the onset of sporadic breast cancers linked to silencing of the BRCA-1 gene.