Factors associated with variability in DNA repair capacity in their effect on bre

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DESCRIPTION (provided by applicant): Breast cancer is a complex disease that is caused by multiple factors. Deficits in DNA repair capacity (DRC) are known to cause certain familial breast cancers, and dysregulation of DRC develops with progressive carcinogenesis. However, the effect of DRC on carcinogenesis of sporadic breast tumors has not been well characterized-and the factors associated with DRC variability are still poorly understood. DNA repair is integral to maintaining genomic integrity, and carcinogenesis occurs when efficient, effective DNA repair is impaired. Thus, we believe that studying DRC in women without and with breast cancer (BC) will provide critical new information to help predict breast cancer risk and its risk of recurrence Identifying phenotypic, epigenetic, and epidemiological factors that can be used as diagnostic or prognostic indicators holds great value for improving human health in relation to breast cancer prevention and therapy. We have shown that a wide range of DRC variability exists in the large cohort of women we have been studying since 2006, which alludes to DRC being influenced by genetic, environmental, and epigenetic factors. Identifying what causes that variability will bring us closer to finding new, clinically relevant biomarkers for breast cancer. To that end, we hypothesize that (1) low DRC is a predictor of breast cancer risk and recurrence, and that (2) certain genetic and epigenetic factors directly influence DRC variability. Our three aims will test these hypotheses, with the ultimate goal of uncovering new information that can expand the repertoire of predictive and prognostic biomarkers for breast cancer through the use of simple blood tests. Our first aim will test the hypothesis that a low DRC is a predictor of breast cancer risk and recurrence by utilizing the cohort of 1,083 women recruited in our ongoing study. We will do this by utilizing a method that tests for a particular DNA repair pathway (the Nucleotide Excision Repair pathway) that has been shown to be deficient in women with BC. The second aim evaluates the relationship of DRC and hormone receptor status, which, if validated, would represent a genetic influence on BC. We hypothesize that BC patients with HER2/neu or progesterone receptors are more likely to have a low DRC than patients with estrogen receptors. We also will explore whether BC patients with double- and triple-negative receptors have greater odds of a low DRC. In the third aim, we will study two epigenetic mechanisms that may be partly responsible for the DRC impairment that we have found in women with BC. Using a candidate gene approach, we will study (1) methylation patterns of certain DNA repair gene promoters and (2) levels of expression of selected miRNAs. We hypothesize that abnormal methylation of gene promoters and altered expression of miRNAs contributes to a low DRC (and thus, increases the risk of developing primary or recurrent BC). As a side benefit to this research, all these tests are done on blood samples. If our hypotheses are correct, our work could lead to new, simple, non-invasive screening tests for breast cancer.