Abstract

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.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA083752-02
Application #
6377551
Study Section
Metabolic Pathology Study Section (MEP)
Program Officer
Yang, Shen K
Project Start
2000-07-04
Project End
2004-06-30
Budget Start
2001-07-01
Budget End
2002-06-30
Support Year
2
Fiscal Year
2001
Total Cost
$272,700
Indirect Cost

  Institution

Name
Vanderbilt University Medical Center
Department
Pathology
Type
Schools of Medicine
DUNS #
004413456
City
Nashville
State
TN
Country
United States
Zip Code
37212

  Publications

Parl, Fritz F; Dawling, Sheila; Roodi, Nady et al. (2009) Estrogen metabolism and breast cancer: a risk model. Ann N Y Acad Sci 1155:68-75
Bradley, Chastity; van der Meer, Riet; Roodi, Nady et al. (2007) Carcinogen-induced histone alteration in normal human mammary epithelial cells. Carcinogenesis 28:2184-92
Belous, Alexandra R; Hachey, David L; Dawling, Sheila et al. (2007) Cytochrome P450 1B1-mediated estrogen metabolism results in estrogen-deoxyribonucleoside adduct formation. Cancer Res 67:812-7
Crooke, Philip S; Ritchie, Marylyn D; Hachey, David L et al. (2006) Estrogens, enzyme variants, and breast cancer: a risk model. Cancer Epidemiol Biomarkers Prev 15:1620-9
Sanders, Melinda E; Schuyler, Peggy A; Dupont, William D et al. (2005) The natural history of low-grade ductal carcinoma in situ of the breast in women treated by biopsy only revealed over 30 years of long-term follow-up. Cancer 103:2481-4
Parl, Fritz F (2005) Glutathione S-transferase genotypes and cancer risk. Cancer Lett 221:123-9
Dawling, Sheila; Hachey, David L; Roodi, Nady et al. (2004) In vitro model of mammary estrogen metabolism: structural and kinetic differences between catechol estrogens 2- and 4-hydroxyestradiol. Chem Res Toxicol 17:1258-64
Roodi, Nady; Dupont, William D; Moore, Jason H et al. (2004) Association of homozygous wild-type glutathione S-transferase M1 genotype with increased breast cancer risk. Cancer Res 64:1233-6
Dawling, Sheila; Roodi, Nady; Parl, Fritz F (2003) Methoxyestrogens exert feedback inhibition on cytochrome P450 1A1 and 1B1. Cancer Res 63:3127-32
Hachey, David L; Dawling, Sheila; Roodi, Nady et al. (2003) Sequential action of phase I and II enzymes cytochrome p450 1B1 and glutathione S-transferase P1 in mammary estrogen metabolism. Cancer Res 63:8492-9

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