Telomere dysfunction, oxidative damage and breast cancer risk

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DESCRIPTION (provided by applicant): Telomeres are specialized DNA-protein structures at the ends of linear chromosomes, and are essential for maintaining the integrity and stability of the genome. Telomere dysfunction can lead to genomic instability that in turn drives the tumorigenic process in pre-malignant breast lesions and normal breast tissues. Several genetic or environmental factors may affect telomere dysfunction, and modify breast cancer risk: (1) progressive loss of telomere repeat sequences due to the problem of replicating chromosome ends; (2) oxidative damage to telomeric DNA accelerating telomere shortening; (3) disruption of higher-order telomere structures due to defects in various telomere-binding proteins; (4) age, cigarette smoking, chronic inflammation and epigenetic modifications, etc. But there is little evidence from population studies. The broad and long-term objectives of the study are to clarify the etiological role of telomere dysfunction in breast cancer risk and the potential determinants for shortened telomeres. The specific aims of the present study are to: (1) Explore the association between telomere dysfunction and breast cancer risk in a large population-based case-control study - the Long Island Breast Cancer Study Project (LIBCSP). (2) Evaluate the modifying effects of oxidative damage (urinary 15-F2t-lsoP and 8-oxodG levels as biomarkers) and antioxidant capacity (antioxidants intake levels obtained from FFQ) on telomere dysfunction for breast cancer risk. (3) Screen for SNPs in key telomere stability genes that potential affect telomere function. Associations between 96 SNPs and shortening telomere, breast cancer risk will be determined. Quantitative PCR (Q-PCR) will be used to measure telomere length in peripheral blood lymphocytes (PBLs) among 800 cases and 800 controls as a biomarker of telomere dysfunction; Urinary 15-F2t-lsoP levels will be analyzed using immunoassay kits. Urinary 8-oxodG levels will be analyzed by competitive ELISA. The high through-put SNPIexTM genotyping system will be used to genotyped potential functional SNPs in key telomere stability genes. Understanding the role of telomere dysfunction in breast cancer risk and the modifying effect of oxidative damage and antioxidant capacity has important implications for improved preventive, diagnostic and treatment strategies for breast cancer.