Comparative Biology of Brea2 Gene Expression in Caucasian and African American Female Breast Cells
Abstract
The overall goal of this proposed project is to understand the mechanism of regulation of human BRCA2 gene expression in order to explore the possibility of epigenetic malfunction in this mechanism, which may lead to sporadic breast cancer. The majority (>95%) of human breast cancer happens sporadically and caused by mutations in a variety of genes (1-5). On the other hand, the familial breast cancers are caused by the defects in either of the two DNA repair protein genes, BRCA1 and BRCA2 (1). Possibility of epigenetic malfunction in the expression of these genes in developing sporadic breast cancer has been proposed. BRCA2 mRNAs were only detected in dividing cells but not at all in quiescent cells (1-5). Recently, we have found an Alu-repeat containing transcriptional silencer at the upstream of human BRCA2 gene (6). This silencer is active only in the quiescent cells but not in the dividing breast cells, thus explaining the absence of BRCA2 mRNA in the quiescent cells. The mechanisms of that activation and inactivation of this silencer in the quiescent and dividing cells, respectively, are presently unknown. We have shown that specific nuclear proteins from quiescent breast cell nuclear extract sequence-specifically binds to this silencer (6). Understanding the structure-activity relationships in these bindings in reference to covalent modifications of the DNA elements and the protein factors may reveal the mechanisms of the regulation of the silencer function. Thus, we believe that the human BRCA2 gene is silenced in the quiescent stage of breast cells but is activated in the dividing cells by the inactivation of an Alu-containing silencer located at the upstream of the BRCA2 gene promoter. Possible transient epigenetic malfunction in this silencer inactivation process by environmental factors in the dividing cells may lead to defect in DNA repair and subsequence onset of mutations in any key gene leading to oncogenesis.
Document Details
- Document Type
- Technical Report
- Publication Date
- Jun 01, 2003
- Accession Number
- ADA418109
Entities
People
- Gautam Chaudhuri
Organizations
- Meharry Medical College