Carcinogenesis Advance Access published online on April 21, 2005
Carcinogenesis, doi:10.1093/carcin/bgi093
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1 Cancer Registry and Molecular Epidemiology, University Hospital, Vogelsangstr. 10, 8091 Zurich, Switzerland
* To whom correspondence should be addressed. Cyclin D1 (CCND1), an intracellular cell cycle regulatory protein with checkpoint function, can promote cell proliferation or induce growth arrest and apoptosis depending on the cellular context. We hypothesized that the direction of the association between the (CCND1) G870A-polymorphism and breast cancer risk may be modified by dietary and genetic factors influencing the oxidant-antioxidant balance, such as a dietary pattern with a high intake of n_6 fatty acids and a low intake of n_3 fatty acids, or a genetic profile that is deficient in glutathione S-transferases. We tested our hypothesis in a case-control study nested into the Singapore Chinese Health Study, a prospective investigation of diet and cancer in 63,000 Chinese men and women. Genomic DNA collected from 258 incident breast cancer cases and 670 female cohort controls was examined for CCND1, GSTM1, GSTT1 and GSTP1 genes using fluorogenic 5'-nuclease assay. Unconditional logistic regression models were used to assess the effects with adjustment for potential confounders. All statistical tests were 2-sided. The heterozygous CCND1 GA genotype significantly reduced the breast cancer risk in all subjects (OR=0.67, 95%CI 0.45-0.99) when compared with the GG genotype. The association was restricted to women with a high (above median value) intake level of n_6 fatty acids (OR= 0.51, 95%CI 0.30-0.87), a low (below median value) intake level of the antagonistic marine n_3 fatty acids (OR= 0.54, 95%CI 0.32-0.93), or a total lack of the antioxidative GSTM1 (OR= 0.44; 95%CI 0.25-0.80) or GSTT1 genes (OR= 0.46; 95%CI 0.24-0.87). The effects were consistently stronger in cases with advanced disease. The AA genotype did not affect breast cancer risk. The results of this study are compatible with the hypothesis that the oxidant-antioxidant balance in cells is an important determinant of the direction of the cyclin D1 effect, leading either to cell proliferation or cell death.
Received December 3, 2004
Revised March 18, 2005
Accepted April 10, 2005
CARCINOGENESIS
The effect of cyclin D1 (CCND1) G870A-polymorphism on breast cancer risk is modified by oxidative stress among Chinese women in Singapore
2 University of Minnesota Cancer Center, Minneapolis, Minnesota 55455
3 USC/Norris Comprehensive Cancer Center, University of Southern California Keck School of Medicine, Los Angeles, California 90033-0800
4 Department of Community, Occupational and Family Medicine, Faculty of Medicine, National University of Singapore, Singapore 117597
Nicole Probst-Hensch, E-mail: Nicole.Probst{at}usz.ch
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