MOLECULAR REGULATION OF THE HUMAN BRCA 1 GENE

DESCRIPTION: The central hypothesis is that PAHs may contribute to breast carcinogenesis through the inhibition of BRCA-1 expression. The loss of BRCA-1 may lead to accumulation of DNA damage critical for tumor development. The long-range goal of this project is to investigate the role of gene-environment interactions in the etiology of sporadic breast cancer. The objectives of this application are 1) to dissect the molecular regulation of the tumor suppressor BRCA-1 by polycyclic aromatic hydrocarbons (PAHs); 2) investigate the contribution of the estrogen receptor (ER)/Sp1 pathways in BRCA-1 regulation by PAHs; and 3) examine the relationship between loss of BRCA-1 and accumulation of DNA damage. The applicants propose that the mechanism through which PAHs may disrupt BRCA-1 expression is through binding of the PAH-aromatic hydrocarbon receptor (AhR) heterocomplex to one or more xenobiotic response elements (XRE) located in the proximal promoter regions of the BRCA-1 gene. The occupancy of the XRE by the AhR-heterocomplex may interfere with basal and regulated transcription of BRCA-1 from a subset of cis-acting estrogen receptor (ER) and Sp1 sites located in close proximity of the XRE. The applicants postulate that the degree of damage caused by PAHs is a function of 1) intensity and duration of exposure, and 2) ER status. At non-cytotoxic concentrations (=chronic exposure), PAHs may contribute to breast tumorigenesis through chronic inhibition of DNA functions requiring BRCA-1, thus favoring the fixation of mutations. The exposure to cytotoxic concentrations of PAHs (=acute exposure) may allow proliferation of resistant cells with BRCA-1 null phenotype containing mutations or chromosomal aberrations. The applicants hypothesize that the ER/Sp1 may play a role as endogenous factors through a synergism with the AhR pathway. Specific aim #1 will examine whether the XREs function as negative transcription elements. Specific aim #2 will investigate the cross-talk between the AhR/XRE and ER/Sp1 pathways in the regulation of BRCA-1 transcription. Specific aim #3 will examine the function of BRCA-1 in cell cycle regulation at different levels of genotoxic damage induced by PAHs.