The role of oxidative stress, XRCC1 genotype, and DNA repair phenotype in breast cancer

Estrogen is an important initiator and promoter of breast cancer. Estrogen is a potent mitogen, and its metabolism generates reactive oxygen species (ROS) that can modify cellular macromolecules. ROS produce carbonyl groups on amino acid side chains and reacts with DNA to form oxidized bases, the most common of which is 8-hydroxy-2-deoxyguanosine (8-oxodG). Unrepaired 8-oxodG lesions can produce G to T transversions that may be involved in the initiation of carcinogenesis. XRCC1 is involved in the repair of oxidative DNA damage, and has several gene variants that may influence individual susceptibility to breast cancer by altering DNA repair capacity in the presence of ROS.; While several breast cancer risk factors can be assessed reliably by questionnaire, biological measures that integrate exposures relevant to carcinogenesis may provide additional information about risk. In this thesis, we explored the potential of biomarkers of oxidative stress, and DNA repair in predicting breast cancer risk, and the role of gene variants in conferring susceptibility to breast cancer. Biological specimens from breast cancer cases and controls participating in the Metropolitan New York Breast Cancer Family Registry were used in all analyses.; BMI, parity, race, HRT use, and age at menarche contributed to plasma protein carbonyl levels. In addition, plasma protein carbonyls and urinary 8-oxodG levels were independently associated with an increase in breast cancer risk. Three gene variants in XRCC1 were explored in association with breast cancer risk, XRCC1 R194W, R280H, and R399Q. The XRCC1 399Gln variant and CGA haplotype were associated with a non-significant decrease in breast cancer risk while the XRCC1 194Trp variant and the TGG haplotype were associated with a non-significant increase in breast cancer risk. in vitro experiments revealed that XRCC1 mRNA levels were significantly increased in XRCC1 399Gln lymphoblastoid cells compared with XRCC1 399Arg lymphblastoid cells from healthy subjects. There was a corresponding increase in nicking activity on a substrate containing a UG mispair in nuclear extracts from XRCC1 399Gln lymphoblastoid cell lines, though this difference was not statistically significant.; These results suggest that biological markers of susceptibility and exposure may be useful in identifying individuals at risk for breast cancer.