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Estrogen Metabolism–Related Genes and Breast Cancer Risk: The Multiethnic Cohort Study

¹ Etiology Program, Cancer Research Center of Hawaii, University of Hawaii, Honolulu, Hawaii and ² Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, California

Requests for reprints: Loïc Le Marchand, Etiology Program, Cancer Research Center of Hawaii, University of Hawaii, Suite 407, 1236 Lauhala Street, Honolulu, HI 96813. Phone: 808-586-2988; Fax: 808-586-2082. E-mail: loic{at}crch.hawaii.edu

Common polymorphisms in genes that affect estrogen levels may be associated with breast cancer risk. We investigated the associations between breast cancer and sequence variants in several genes in the estradiol/estrone metabolism pathway (CYP1A1*2A, CYP1A2*1F, CYP1B1 Leu⁴³²Val, CYP3A4*1B, COMT Val¹⁵⁸Met, SULT1A1Arg²¹³His) as well as the Arg⁵⁵⁴Lys variant in AHR (a transcription factor for CYP1A1, CYP1A2, and CYP1B1) in a case-control study of 1,339 breast cancer cases and 1,370 controls nested in the Multiethnic Cohort Study. The Multiethnic Cohort Study is a large prospective study of men and predominantly postmenopausal women of Japanese, White, African American, Latino, and Native Hawaiian ancestry, residing in Hawaii and Los Angeles. We found no association between breast cancer and these polymorphisms, except for CYP1A2*1F which was inversely associated with risk. The odds ratio (95% confidence interval) for the AA, AC, and CC genotype was 1.0, 0.9 (0.7-1.0), and 0.7 (0.5-1.0), respectively (P for gene dosage effect = 0.03). This association seemed somewhat stronger for estrogen receptor (ER)/progesterone receptor (PR)–negative tumors than for ER/PR-positive tumors, and no statistically significant interaction with estrogen-related risk factors was detected. The findings provide no evidence for a role of COMT Val⁵⁸Met, CYP1A1*2A, CYP3A4*1B, CYP1B1 Leu⁴³²Val, SULT1A1 Arg²¹³His, and AHR Arg⁵⁵⁴Lys in breast cancer etiology. They also provide support for an inverse association between CYP1A2*1F and breast cancer, which is consistent with the observation of lower circulating estrogen levels in premenopausal women with the CC genotype in a previous study.

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