Mammary estrogen metabolism leads to the formation of catechol estrogens, the 2-OH and 4-OH derivatives of 17beta-estradiol (E2) and estrone (E1). These catechol estrogens can directly or indirectly induce DNA damage and have been implicated as a cause of breast cancer. The PI hypothesizes that differences in breast cancer risk between individuals are due in part to the individual-specific metabolism of catechol estrogens. In normal breast tissue and in breast tumors, catechol estrogens are produced by cytochromes P450 1A1 (CYP1A1) and 1B1 (CYP1B1) and are inactivated by catechol-O-methyltransferase (COMT). These enzymes exist as wild type forms and several polymorphic variants which may determine catechol estrogen exposures and resultant breast cancer risk in individual women.
Aim 1 is to determine whether amino acid substitutions in CYP1A1, CYP1B1, and COMT affect estrogen metabolism using express recombinant forms of these enzymes.
Aim 2 is to determine the effect of CYP1A1, CYP1B1, and COMT variant on estrogen metabolism in cultured cells, and to determine the relative inducibility of wild-type and variant forms of enzymes CYP1A1, CYP1B1, and COMT.
Aim 3 is to determine the relationship between CYP1A1, CYP1B1, and COMT genotypes and catechol estrogen levels in benign and malignant human breast tissue. The applicants will measure catechol estrogens in tissues selected by genotype and matched by menopausal status and body mass index and compare the results to those in their in vitro and cell line experiments.
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