Genetic Determinants of Aromatase Expression and Susceptibility to Postmenopausal Breast Cancer

摘要

The major source of estrogen in postmenopausal women is conversion of androstenedione in adipose tissue to estrone by the enzyme aromatase. In adipose tissue, the aromatase gene, CYP19, is regulated by the cytokines TNF-alpha and IL-6. The objective of this study was to determine whether polymorphism in the TNF-alpha gene, in the IL-6 gene, or in the regulatory region of the CYP19 gene is associated with the plasma estrone (El) to androstenedione (A) ratio, a measure of peripheral estrogen production, or with risk of post-menopausal breast cancer. This investigation was carried out using DNA and serum samples from women enrolled in the Hawaii-Los Angeles Multiethnic cohort study. We found that among African-American women, but not among other women, polymorphisms in both the TNF-alpha and IL-6 genes were associated with increased breast cancer risk after stratification on obesity. Increasing weight also appeared to be associated with increased peripheral estrogen production among women with high- inducibility TNF alpha genotypes but not among other women. Because our findings were not consistent across ethnic groups and because they were based on relatively small numbers of women within each ethnic group, we are attempting to confirm these results in a second multi-ethnic population.