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Carcinogenesis Advance Access published online on October 21, 2004
Carcinogenesis, doi:10.1093/carcin/bgh309
© 2004 by Oxford University Press
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Received August 28, 2004
Revised September 30, 2004
Accepted October 1, 2004

MOLECULAR EPIDEMIOLOGY AND CANCER PREVENTION

Polymorphisms in angiotensin II type 1 receptor (AGTR1) and angiotensin I-converting enzyme (ACE) genes and breast cancer risk among chinese women in Singapore

Woon-Puay Koh 1*, Jian-Min Yuan 2, David Van Den Berg 2, Hin-Peng Lee 1, and Mimi C. Yu 2

1 Department of Community, Occupational and Family Medicine, National University of Singapore, 16 Medical Drive, Singapore 117597, Singapore
2 USC/Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, California 90033-0800

* To whom correspondence should be addressed.
Woon-Puay Koh, E-mail: cofkwp{at}nus.edu.sg


  Abstract

Angiotensin II is converted from its precursor by angiotensin I-converting enzyme (ACE), and has been shown to mediate growth effect in breast cancer cell lines via its ligand-induced activity through the angiotensin II type 1 receptor (AGTR1). Earlier, we have shown that women with the low-activity genotype of the ACE gene are at a statistically significant ~50% reduction in breast cancer risk compared with those possessing the high-activity ACE genotype. To further test the hypothesis that angiotensin II participates in breast carcinogenesis through AGTR1, we examined genetic polymorphisms in the 5' region of the AGTR1 gene, A-168G, C-535T and T-825A, in relation to risk of breast cancer on 258 breast cancer cases and 670 female controls within the Singapore Chinese Health Study. Relative to the homozygotes, individual genotypes with one or two copies of the respective allelic variants (putative low risk genotypes) were each associated with ~30% reduction in risk of breast cancer. Risk of breast cancer decreased with increasing number of low-risk AGTR1 genotypes after adjustment for potential confounders. Relative to those carrying no low-risk genotypes (homozygous for A, C and T alleles for the three polymorphisms, respectively); the odds ratios (95% confidence intervals) were 0.84 (0.51-1.37) for women possessing one low-risk genotype and 0.68 (0.46-1.01) for women possessing two or three low-risk genotypes (P for trend = 0.05). When both AGTR1 and ACE gene polymorphisms were examined simultaneously, women possessing at least one AGTR1 low-risk genotype in combination with the ACE low-activity genotype had an odds ratio of 0.35 (95% confidence interval, 0.20-0.62) compared with those possessing the ACE high-activity genotype and no AGTR1 low-risk genotype. Our findings suggest that pharmacological inhibition of the angiotensin II effect by blockade of ACE and/or AGTR1 can be potential targets for the prevention and treatment of breast cancer.

Keywords: Angiotensin II type 1 receptor; Angiotensin I-converting enzyme; breast cancer; genotype.
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