Role of estradiol metabolism and CYP1A1 polymorphisms in breast cancer risk.
The endogenous metabolism of estrogens is primarily oxidative and involves hydroxylation of the steroid at either C2 (2-OHE1) or C16 (16-OHE1). While the 2-OHE1 metabolites are essentially devoid of peripheral biological activity, 16-OHE1 is an estrogen agonist. There is evidence of an association between the 2-OHE1/16-OHE1 metabolites ratio and breast cancer risk. The CYP1A1 gene may play a role in the 2-hydroxylation (2-OH) of estradiol. African-American women with the wild-type CYP1A1 gene showed a significant increase in the 2-OHE1/16-OHE1 ratio, from 1.35 +/- 0.56 at baseline to 2.39 +/- 0.98 (p = 0.006) after 5 days of treatment with indole-3-carbinol (400 mg/day), a 2-OHE1 inducer. Women with the Msp1 polymorphism showed no significant increase, (0.37% +/- 0.17%). In a case-control study involving 57 women with breast cancer and 312 female controls, the frequency of the homozygous Msp1 polymorphism was 4.2% in African-American controls and 16% in African-American breast cancer cases. The odds ratio of breast cancer with the Msp1 homozygous variant was 8.4 (95% confidence interval: 1.7-41.7). This association was not observed in Caucasian women. The other CYP1A1 polymorphisms were not associated with breast cancer. The CYP1A1 Msp1 polymorphism may be a marker of altered estradiol metabolism and of increased susceptibility to estrogen-related breast cancer in African-Americans.
Taioli
E
E
Institute of Environmental Medicine, New York University Medical Center, New York, NY 10016, USA.
Bradlow
H L
HL
Garbers
S V
SV
Sepkovic
D W
DW
Osborne
M P
MP
Trachman
J
J
Ganguly
S
S
Garte
S J
SJ
D000328:Adult; D044383:Black People / Q000235:genetics; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism*; D016022:Case-Control Studies; D019363:Cytochrome P-450 CYP1A1 / Q000235:genetics*; D004958:Estradiol / Q000378:metabolism* / Q000502:physiology; D004965:Estrogen Antagonists / Q000494:pharmacology; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D005838:Genotype; D006801:Humans; D006894:Hydroxyestrones / Q000378:metabolism; D007211:Indoles / Q000494:pharmacology; D008297:Male; D008875:Middle Aged; D011110:Polymorphism, Genetic; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D012307:Risk Factors; D044465:White People / Q000235:genetics; D001741:Black or African American
D004965:Estrogen Antagonists; D006894:Hydroxyestrones; D007211:Indoles; D012333:RNA, Messenger; C026702:16-hydroxyestrone; D004958:Estradiol; C016517:indole-3-carbinol; D019363:Cytochrome P-450 CYP1A1; C024980:2-hydroxyestrone