Comparataive Biology of BRCA2 Gene Expression in Caucasian and African- American Female Breast Cells

摘要

The overall goal of this 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 BRCA2 mRNAs were only detected in dividing cells but not at all in quiescent cells. We have found a transcriptional silencer at the upstream of human BRCA2 gene. 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 the 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. We also have observed that at least some of the African-American breast cells may have alteration in this regulatory pathway. We hypothesize 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 the silencer. 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. Our studies may relate this regulatory pathway with respect to the ethnic origin of the breast cells.