This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Huang, C.-S. Articles by Shen, C.-Y. Search for Related Content PubMed PubMed Citation Articles by Huang, C.-S. Articles by Shen, C.-Y.

Breast Cancer Risk Associated with Genotype Polymorphism of the Estrogen-metabolizing Genes CYP17, CYP1A1, and COMT

A Multigenic Study on Cancer Susceptibility

Departments of Surgery [C-S. H., K-J. C.] and Pathology [S-M. S.], National Taiwan University Hospital, Taipei, Taiwan; Graduate Institute of Pharmaceutical Sciences, College of Medicine, National Taiwan University, Taipei, Taiwan [H-D. C., C-W. C.]; and Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan [C-W. C., C-Y. S.]

Estrogen has been proposed to trigger breast cancer development via an initiating mechanism involving its metabolite, catechol estrogen (CE). To examine this hypothesis, we conducted a multigenic case-control study to determine whether polymorphisms of the genes responsible for CE formation via estrogen biosynthesis (CYP17) and hydroxylation (CYP1A1) and CE inactivation (COMT) are associated with an elevated risk for breast cancer in Taiwanese women, and whether the association between genotype and risk may be modified by estrogen exposure. One hundred and fifty breast cancer patients and 150 healthy controls were recruited. PCR-based RFLP assays were used to determine the genotypes of estrogen-metabolizing genes. The breast cancer risk associated with individual susceptibility genotypes varied among the three genes and was highest for COMT, followed by CYP1A1 and CYP17. After simultaneous consideration of all three genes and other well-established risk factors of breast cancer, the COMT genotype remained the most significant determinant for breast cancer development and was associated with a 4-fold increase in risk (95% confidence interval, 1.12–19.08). Furthermore, a trend of increasing risk for developing breast cancer was found in women harboring higher numbers of high-risk genotypes (P = 0.006), including the high activity CYP17 (CYP17 A₂/A₂), high inducibility CYP1A1 (CYP1A1 MspI vt/vt), and low activity COMT (COMT L/L) genotypes. The association of risk with the number of susceptibility genotypes was stronger in women with prolonged estrogen exposure (indicated by a higher number of estrogen exposure years or a higher number of estrogen exposure years between menarche and first full-term pregnancy), women with higher estrogen levels (implied by early menarche), and women with a higher body mass index (22.5). On the basis of comprehensive profiles of estrogen metabolism, this study supports the possibility that breast cancer can be initiated by estrogen exposure.

This article has been cited by other articles:

				J.-C. Yu, S.-l. Ding, C.-H. Chang, S.-H. Kuo, S.-T. Chen, G.-C. Hsu, H.-M. Hsu, M.-F. Hou, L. Y. Jung, C.-W. Cheng, et al. Genetic susceptibility to the development and progression of breast cancer associated with polymorphism of cell cycle and ubiquitin ligase genes Carcinogenesis, September 1, 2009; 30(9): 1562 - 1570. [Abstract] [Full Text] [PDF]

				X. Yuan, G. Zhou, Y. Zhai, W. Xie, Y. Cui, J. Cao, L. Zhi, H. Zhang, H. Yang, X. Zhang, et al. Lack of Association between the Functional Polymorphisms in the Estrogen-Metabolizing Genes and Risk for Hepatocellular Carcinoma Cancer Epidemiol. Biomarkers Prev., December 1, 2008; 17(12): 3621 - 3627. [Abstract] [Full Text] [PDF]

				C.-S. Huang, S.-H. Kuo, H.-C. Lien, S.-Y. Yang, S.-L. You, C.-Y. Shen, C.-H. Lin, Y.-S. Lu, and K.-J. Chang The CYP19 TTTA Repeat Polymorphism Is Related to the Prognosis of Premenopausal Stage I-II and Operable Stage III Breast Cancers Oncologist, July 1, 2008; 13(7): 751 - 760. [Abstract] [Full Text] [PDF]

				Y. Chen, M. D. Gammon, S. L. Teitelbaum, J. A. Britton, M. B. Terry, S. Shantakumar, S. M. Eng, Q. Wang, I. Gurvich, A. I. Neugut, et al. Estrogen-biosynthesis gene CYP17 and its interactions with reproductive, hormonal and lifestyle factors in breast cancer risk: results from the Long Island Breast Cancer Study Project Carcinogenesis, April 1, 2008; 29(4): 766 - 771. [Abstract] [Full Text] [PDF]

				L. Lehmann, L. Jiang, and J. Wagner Soy isoflavones decrease the catechol-O-methyltransferase-mediated inactivation of 4-hydroxyestradiol in cultured MCF-7 cells Carcinogenesis, February 1, 2008; 29(2): 363 - 370. [Abstract] [Full Text] [PDF]

				S. Hassan, A. Baccarelli, O. Salvucci, and M. Basik Plasma Stromal Cell-Derived Factor-1: Host Derived Marker Predictive of Distant Metastasis in Breast Cancer Clin. Cancer Res., January 15, 2008; 14(2): 446 - 454. [Abstract] [Full Text] [PDF]

				H.-M. Hsu, H.-C. Wang, S.-T. Chen, G.-C. Hsu, C.-Y. Shen, and J.-C. Yu Breast Cancer Risk Is Associated with the Genes Encoding the DNA Double-Strand Break Repair Mre11/Rad50/Nbs1 Complex Cancer Epidemiol. Biomarkers Prev., October 1, 2007; 16(10): 2024 - 2032. [Abstract] [Full Text] [PDF]

				D.-T. Bau, Y.-C. Mau, S.-l. Ding, P.-E. Wu, and C.-Y. Shen DNA double-strand break repair capacity and risk of breast cancer Carcinogenesis, August 1, 2007; 28(8): 1726 - 1730. [Abstract] [Full Text] [PDF]

				Y.-L. Lo, J.-C. Yu, S.-T. Chen, G.-C. Hsu, Y.-C. Mau, S.-L. Yang, P.-E. Wu, and C.-Y. Shen Breast cancer risk associated with genotypic polymorphism of the mitotic checkpoint genes: a multigenic study on cancer susceptibility Carcinogenesis, May 1, 2007; 28(5): 1079 - 1086. [Abstract] [Full Text] [PDF]

				T. R. Rebbeck, A. B. Troxel, A. H. Walker, S. Panossian, S. Gallagher, E. G. Shatalova, R. Blanchard, S. Norman, G. Bunin, A. DeMichele, et al. Pairwise Combinations of Estrogen Metabolism Genotypes in Postmenopausal Breast Cancer Etiology Cancer Epidemiol. Biomarkers Prev., March 1, 2007; 16(3): 444 - 450. [Abstract] [Full Text] [PDF]

				K. M. Gooden, J. C. Schroeder, K. E. North, M. D. Gammon, K. E. Hartmann, J. Taylor, and D. D. Baird Val153Met Polymorphism of Catechol-O-Methyltransferase and Prevalence of Uterine Leiomyomata Reproductive Sciences, February 1, 2007; 14(2): 117 - 120. [Abstract] [PDF]

				G. Jasienska, M. Kapiszewska, P. T. Ellison, M. Kalemba-Drozdz, I. Nenko, I. Thune, and A. Ziomkiewicz CYP17 Genotypes Differ in Salivary 17-{beta} Estradiol Levels: A Study Based on Hormonal Profiles from Entire Menstrual Cycles. Cancer Epidemiol. Biomarkers Prev., November 1, 2006; 15(11): 2131 - 2135. [Abstract] [Full Text] [PDF]

				Y. Tanaka, M. Sasaki, H. Shiina, T. Tokizane, M. Deguchi, H. Hirata, Y. Hinoda, N. Okayama, Y. Suehiro, S. Urakami, et al. Catechol-O-methyltransferase Gene Polymorphisms in Benign Prostatic Hyperplasia and Sporadic Prostate Cancer. Cancer Epidemiol. Biomarkers Prev., February 1, 2006; 15(2): 238 - 244. [Abstract] [Full Text] [PDF]

				Y. Shen, D.-K. Li, J. Wu, Z. Zhang, and E. Gao Joint Effects of the CYP1A1 MspI, ER{alpha} PvuII, and ER{alpha} XbaI Polymorphisms on the Risk of Breast Cancer: Results from a Population-Based Case-Control Study in Shanghai, China. Cancer Epidemiol. Biomarkers Prev., February 1, 2006; 15(2): 342 - 347. [Abstract] [Full Text] [PDF]

				R. C. Millikan, J. S. Player, A. R. deCotret, C.-K. Tse, and T. Keku Polymorphisms in DNA Repair Genes, Medical Exposure to Ionizing Radiation, and Breast Cancer Risk Cancer Epidemiol. Biomarkers Prev., October 1, 2005; 14(10): 2326 - 2334. [Abstract] [Full Text] [PDF]

				C. F. Skibola, P. M. Bracci, R. A. Paynter, M. S. Forrest, L. Agana, T. Woodage, K. Guegler, M. T. Smith, and E. A. Holly Polymorphisms and Haplotypes in the Cytochrome P450 17A1, Prolactin, and Catechol-O-Methyltransferase Genes and Non-Hodgkin Lymphoma Risk Cancer Epidemiol. Biomarkers Prev., October 1, 2005; 14(10): 2391 - 2401. [Abstract] [Full Text] [PDF]

				L. A. Hefler, C. Grimm, T. Lantzsch, D. Lampe, S. Leodolter, H. Koelbl, G. Heinze, A. Reinthaller, D. Tong-Cacsire, C. Tempfer, et al. Interleukin-1 and Interleukin-6 Gene Polymorphisms and the Risk of Breast Cancer in Caucasian Women Clin. Cancer Res., August 15, 2005; 11(16): 5718 - 5721. [Abstract] [Full Text] [PDF]

				L. F. Masson, L. Sharp, S. C. Cotton, and J. Little Cytochrome P-450 1A1 Gene Polymorphisms and Risk of Breast Cancer: A HuGE Review Am. J. Epidemiol., May 15, 2005; 161(10): 901 - 915. [Abstract] [Full Text] [PDF]

				N. C. Onland-Moret, C. H. van Gils, M. Roest, D. E. Grobbee, and P. H.M. Peeters Cyp17, Urinary Sex Steroid Levels and Breast Cancer Risk in Postmenopausal Women Cancer Epidemiol. Biomarkers Prev., April 1, 2005; 14(4): 815 - 820. [Abstract] [Full Text] [PDF]

				P. Kisselev, W.-H. Schunck, I. Roots, and D. Schwarz Association of CYP1A1 Polymorphisms with Differential Metabolic Activation of 17{beta}-Estradiol and Estrone Cancer Res., April 1, 2005; 65(7): 2972 - 2978. [Abstract] [Full Text] [PDF]

				N. Kurahashi, F. Sata, S. Kasai, T. Shibata, K. Moriya, H. Yamada, H. Kakizaki, H. Minakami, K. Nonomura, and R. Kishi Maternal genetic polymorphisms in CYP1A1, GSTM1 and GSTT1 and the risk of hypospadias Mol. Hum. Reprod., February 1, 2005; 11(2): 93 - 98. [Abstract] [Full Text] [PDF]

				H. S. Kok, N. C. Onland-Moret, K. M. van Asselt, C. H. van Gils, Y. T. van der Schouw, D. E. Grobbee, and P. H.M. Peeters No association of estrogen receptor {alpha} and cytochrome P450c17{alpha} polymorphisms with age at menopause in a Dutch cohort Hum. Reprod., February 1, 2005; 20(2): 536 - 542. [Abstract] [Full Text] [PDF]

				L. Sharp, A. H. Cardy, S. C. Cotton, and J. Little CYP17 Gene Polymorphisms: Prevalence and Associations with Hormone Levels and Related Factors. A HuGE Review Am. J. Epidemiol., October 15, 2004; 160(8): 729 - 740. [Abstract] [Full Text] [PDF]

				D.-T. Bau, Y.-P. Fu, S.-T. Chen, T.-C. Cheng, J.-C. Yu, P.-E. Wu, and C.-Y. Shen Breast Cancer Risk and the DNA Double-Strand Break End-Joining Capacity of Nonhomologous End-Joining Genes Are Affected by BRCA1 Cancer Res., July 15, 2004; 64(14): 5013 - 5019. [Abstract] [Full Text] [PDF]

				M. McGrath, S. E. Hankinson, L. Arbeitman, G. A. Colditz, D. J. Hunter, and I. De Vivo Cytochrome P450 1B1 and catechol-O-methyltransferase polymorphisms and endometrial cancer susceptibility Carcinogenesis, April 1, 2004; 25(4): 559 - 565. [Abstract] [Full Text] [PDF]

				A.-L. Eriksson, S. Skrtic, A. Niklason, L. M. Hulten, O. Wiklund, T. Hedner, and C. Ohlsson Association between the low activity genotype of catechol-O-methyltransferase and myocardial infarction in a hypertensive population Eur. Heart J., March 1, 2004; 25(5): 386 - 391. [Abstract] [Full Text] [PDF]

				A. H. Wu, C.-C. Tseng, D. Van Den Berg, and M. C. Yu Tea Intake, COMT Genotype, and Breast Cancer in Asian-American Women Cancer Res., November 1, 2003; 63(21): 7526 - 7529. [Abstract] [Full Text] [PDF]

				C.-C. Hong, H. J. Thompson, C. Jiang, G. L. Hammond, D. Tritchler, M. Yaffe, and N. F. Boyd Val158Met Polymorphism in Catechol-O-methyltransferase Gene Associated with Risk Factors for Breast Cancer Cancer Epidemiol. Biomarkers Prev., September 1, 2003; 12(9): 838 - 847. [Abstract] [Full Text] [PDF]

				M. Sasaki, M. Kaneuchi, N. Sakuragi, and R. Dahiya Multiple Promoters of Catechol-O-methyltransferase Gene Are Selectively Inactivated by CpG Hypermethylation in Endometrial Cancer Cancer Res., June 15, 2003; 63(12): 3101 - 3106. [Abstract] [Full Text] [PDF]

				Y.-P. Fu, J.-C. Yu, T.-C. Cheng, M. A. Lou, G.-C. Hsu, C.-Y. Wu, S.-T. Chen, H.-S. Wu, P.-E. Wu, and C.-Y. Shen Breast Cancer Risk Associated with Genotypic Polymorphism of the Nonhomologous End-Joining Genes: A Multigenic Study on Cancer Susceptibility Cancer Res., May 15, 2003; 63(10): 2440 - 2446. [Abstract] [Full Text] [PDF]

				S. Wedren, T. R. Rudqvist, F. Granath, E. Weiderpass, M. Ingelman-Sundberg, I. Persson, and C. Magnusson Catechol-O-methyltransferase gene polymorphism and post-menopausal breast cancer risk Carcinogenesis, April 1, 2003; 24(4): 681 - 687. [Abstract] [Full Text] [PDF]

				I. Gorai, K. Tanaka, M. Inada, H. Morinaga, Y. Uchiyama, R. Kikuchi, O. Chaki, and F. Hirahara Estrogen-Metabolizing Gene Polymorphisms, But Not Estrogen Receptor-{alpha} Gene Polymorphisms, Are Associated with the Onset of Menarche in Healthy Postmenopausal Japanese Women J. Clin. Endocrinol. Metab., February 1, 2003; 88(2): 799 - 803. [Abstract] [Full Text] [PDF]

				S. E. McCann, K. B. Moysich, J. L. Freudenheim, C. B. Ambrosone, and P. G. Shields The Risk of Breast Cancer Associated with Dietary Lignans Differs by CYP17 Genotype in Women J. Nutr., October 1, 2002; 132(10): 3036 - 3041. [Abstract] [Full Text] [PDF]

				M M de Jong, I M Nolte, G J te Meerman, W T A van der Graaf, J C Oosterwijk, J H Kleibeuker, M Schaapveld, and E G E de Vries Genes other than BRCA1 and BRCA2 involved in breast cancer susceptibility J. Med. Genet., April 1, 2002; 39(4): 225 - 242. [Abstract] [Full Text] [PDF]

				Z. Ye and J. M. Parry The CYP17 MspA1 polymorphism and breast cancer risk: a meta-analysis Mutagenesis, March 1, 2002; 17(2): 119 - 126. [Abstract] [Full Text] [PDF]

				J. A. Lavigne, J. E. Goodman, T. Fonong, S. Odwin, P. He, D. W. Roberts, and J. D. Yager The Effects of Catechol-O-Methyltransferase Inhibition on Estrogen Metabolite and Oxidative DNA Damage Levels in Estradiol-treated MCF-7 Cells Cancer Res., October 1, 2001; 61(20): 7488 - 7494. [Abstract] [Full Text] [PDF]

				J. E. Goodman, J. A. Lavigne, K. Wu, K. J. Helzlsouer, P. T. Strickland, J. Selhub, and J. D. Yager COMT genotype, micronutrients in the folate metabolic pathway and breast cancer risk Carcinogenesis, October 1, 2001; 22(10): 1661 - 1665. [Abstract] [Full Text] [PDF]

				R. A. Kittles, R. K. Panguluri, W. Chen, A. Massac, C. Ahaghotu, A. Jackson, F. Ukoli, L. Adams-Campbell, W. Isaacs, and G. M. Dunston CYP17 Promoter Variant Associated with Prostate Cancer Aggressiveness in African Americans Cancer Epidemiol. Biomarkers Prev., September 1, 2001; 10(9): 943 - 947. [Abstract] [Full Text] [PDF]

				A. Maitra, I. I. Wistuba, C. Washington, A. K. Virmani, R. Ashfaq, S. Milchgrub, A. F. Gazdar, and J. D. Minna High-Resolution Chromosome 3p Allelotyping of Breast Carcinomas and Precursor Lesions Demonstrates Frequent Loss of Heterozygosity and a Discontinuous Pattern of Allele Loss Am. J. Pathol., July 1, 2001; 159(1): 119 - 130. [Abstract] [Full Text] [PDF]

				K. Mitrunen, N. Jourenkova, V. Kataja, M. Eskelinen, V.-M. Kosma, S. Benhamou, D. Kang, H. Vainio, M. Uusitupa, and A. Hirvonen Polymorphic Catechol-O-methyltransferase Gene and Breast Cancer Risk Cancer Epidemiol. Biomarkers Prev., June 1, 2001; 10(6): 635 - 640. [Abstract] [Full Text] [PDF]

				R. Todorovic, P. Devanesan, S. Higginbotham, J. Zhao, M. L. Gross, E. G. Rogan, and E. L. Cavalieri Analysis of potential biomarkers of estrogen-initiated cancer in the urine of Syrian golden hamsters treated with 4-hydroxyestradiol Carcinogenesis, June 1, 2001; 22(6): 905 - 911. [Abstract] [Full Text] [PDF]

				D. Schwarz, P. Kisselev, I. Cascorbi, W.-H. Schunck, and I. Roots Differential metabolism of benzo[a]pyrene and benzo[a]pyrene-7,8-dihydrodiol by human CYP1A1 variants Carcinogenesis, March 1, 2001; 22(3): 453 - 459. [Abstract] [Full Text] [PDF]

				M. Clemons and P. Goss Estrogen and the Risk of Breast Cancer N. Engl. J. Med., January 25, 2001; 344(4): 276 - 285. [Full Text] [PDF]

				H. S. Feigelson, R. McKean-Cowdin, G. A. Coetzee, D. O. Stram, L. N. Kolonel, and B. E. Henderson Building a Multigenic Model of Breast Cancer Susceptibility: CYP17 and HSD17B1 Are Two Important Candidates Cancer Res., January 1, 2001; 61(2): 785 - 789. [Abstract] [Full Text]

				K. Mitrunen, N. Jourenkova, V. Kataja, M. Eskelinen, V.-M. Kosma, S. Benhamou, H. Vainio, M. Uusitupa, and A. Hirvonen Steroid Metabolism Gene CYP17 Polymorphism and the Development of Breast Cancer Cancer Epidemiol. Biomarkers Prev., December 1, 2000; 9(12): 1343 - 1348. [Abstract] [Full Text]

				J. E. Goodman, J. A. Lavigne, J. G. Hengstler, B. Tanner, K. J. Helzlsouer, and J. D. Yager Catechol-O-Methyltransferase Polymorphism Is Not Associated with Ovarian Cancer Risk Cancer Epidemiol. Biomarkers Prev., December 1, 2000; 9(12): 1373 - 1376. [Abstract] [Full Text]

				A. B. Spurdle, J. L. Hopper, G. S. Dite, X. Chen, J. Cui, M. R. E. McCredie, G. G. Giles, M. C. Southey, D. J. Venter, D. F. Easton, et al. CYP17 Promoter Polymorphism and Breast Cancer in Australian Women Under Age Forty Years J Natl Cancer Inst, October 18, 2000; 92(20): 1674 - 1681. [Abstract] [Full Text] [PDF]

				T. Habuchi, Z. Liqing, T. Suzuki, R. Sasaki, N. Tsuchiya, H. Tachiki, N. Shimoda, S. Satoh, K. Sato, Y. Kakehi, et al. Increased Risk of Prostate Cancer and Benign Prostatic Hyperplasia Associated with a CYP17 Gene Polymorphism with a Gene Dosage Effect Cancer Res., October 1, 2000; 60(20): 5710 - 5713. [Abstract] [Full Text]

				J. A. Williams and D. H. Phillips Mammary Expression of Xenobiotic Metabolizing Enzymes and Their Potential Role in Breast Cancer Cancer Res., September 1, 2000; 60(17): 4667 - 4677. [Abstract] [Full Text]

				C.-Y. Shen, J.-C. Yu, Y.-L. Lo, C.-H. Kuo, C.-T. Yue, Y.-S. Jou, C.-S. Huang, J.-C. Lung, and C.-W. Wu Genome-wide Search for Loss of Heterozygosity Using Laser Capture Microdissected Tissue of Breast Carcinoma: An Implication for Mutator Phenotype and Breast Cancer Pathogenesis Cancer Res., July 1, 2000; 60(14): 3884 - 3892. [Abstract] [Full Text]

				J. D. Yager Chapter 3: Endogenous Estrogens as Carcinogens Through Metabolic Activation J Natl Cancer Inst Monographs, July 1, 2000; 2000(27): 67 - 73. [Abstract] [Full Text] [PDF]

				J. Weisz, G. Fritz-Wolz, S. Gestl, G. A. Clawson, C. R. Creveling, J. G. Liehr, and D. Dabbs Nuclear Localization of Catechol-O-Methyltransferase in Neoplastic and Nonneoplastic Mammary Epithelial Cells Am. J. Pathol., June 1, 2000; 156(6): 1841 - 1848. [Abstract] [Full Text] [PDF]