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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Research Project (R01)
Project #
1R01ES009966-01A2
Application #
6263009
Study Section
Chemical Pathology Study Section (CPA)
Program Officer
Reinlib, Leslie J
Project Start
2001-05-11
Project End
2004-04-30
Budget Start
2001-05-11
Budget End
2002-04-30
Support Year
1
Fiscal Year
2001
Total Cost
$185,770
Indirect Cost
Name
University of Arizona
Department
Veterinary Sciences
Type
Schools of Earth Sciences/Natur
DUNS #
City
Tucson
State
AZ
Country
United States
Zip Code
85721