Association of CYP1B1 gene polymorphisms and the positive expression of estrogen α and estrogen β with endometrial cancer risk

To investigate the relationship between the CYP1B1 L432V polymorphism, ERalpha and ERbeta positivities and the incidence of endometrial cancer. The relationship between CYP1B1 L432V polymorphism, ERalpha and ERbeta positivities and endometrial cancer was investigated using the allele-specific polymerase chain reaction method to analyze gene polymorphism in exon 3 codon 432 (C-G) of CYP1B1. Our results are as follows: in endometrial cancer cases the prevalence rates of CYP1B1 L432V genotypes C/C, C/G, and G/G were 47.2%, 36.1%, and 16.7%, respectively, and 68.8%, 23.8% and 7.5% in the control group, respectively. The frequencies of CYP1B1 C and G alleles were 65.3% and 34.7% in endometrial cancer patients and 80.6% and 19.4% in the control group. A significant difference was found in the genotype distributions or allele frequencies of CYP1B1 L432V polymorphism between the two groups (p < 0.05). Compared with wild-type C/C, the susceptibility of endometrial cancer with homozygotic mutation G/G and heterozygotic mutation C/G increased by 3.235 (95%CI 1.111-9.425) and 2.214 (95% CI 1.067-4.593). Moveover, the positive expression of ERalpha in genotypes G/G and C/G was higher than in the wild genotype C/C (p < 0.05). In conclusion, allelic polymorphism of CYP1B1 L432V increases the risk of endometrial cancer and has a positive correlation with ERalpha expression.

Endometrial cancer; L432V polymorphism of CYP1B1 gene; Risk factor; ERα and ERβ

[1] Buchanan E.M., Weinstein L.C., Hillson C.: “Endometrial cancer”. Am. Fam. Physician, 2009, 80, 1075.

[2] Linkov F., Edwards R., Balk J., Yurkovetsky Z., Stadterman B., Lokshin A., Taioli E.: “Endometrial hyperplasia, endometrial cancer and prevention: gaps in existing research of modifiable risk factors”. Eur. J. Cancer, 2008, 44, 1632.

[3] Purdie D.M., Green A.C.: “Epidemiology of endometrial cancer”. Best Pract. Res. Clin. Obstet. Gynaecol., 2001, 15, 341.

[4] Tsuchiya Y., Nakajima M., Yokoi T.: “Cytochrome P450-mediated metabolism of estrogens and its regulation in human”. Cancer Lett., 2005, 227, 115.

[5] Goodman M.T., McDuffie K., Kolonel L.N., Terada K., Donlon

T. A., Wilkens L.R. et al.: “Case-control study of ovarian cancer and polymorphisms in genes involved in catecholestrogen formation and metabolism”. Cancer Epidemiol. Biomarkers Prev., 2001, 10, 209.

[6] Tsuchiya Y., Nakajima M., Kyo S, Kanaya T, Inoue M., Yokoi T.: “Human CYP1B1 is regulated by estradiol via estrogen receptor”. Cancer Res., 2004, 64, 3119.

[7] Sasaki M., Kaneuchi M., Fujimoto S., Tanaka Y., Dahiya R.: “CYP1B1 gene in endometrial cancer”. Mol. Cell Endocrinol., 2003, 202, 171.

[8] Zhu Z.Y., Mi R.R., Liu J.: “Association between gene polymorphism of CYP1B1 and susceptibility to ovarian cancer”. Progress Obstet. Gynecol., 2006, 15, 184.

[9] Tanaka Y., Sasaki M., Kaneuchi M., Shiina H., Igawa M., Dahiya R.: “Polymorphisms of the CYP1B1 gene have higher risk for prostate cancer”. Biochem. Biophys Res. Commun., 2002, 296, 820.

[10] Okobia M.N., Bunker C.H., Garte S.J., Zmuda J.M., Ezeome E.R., Anyanwu S.N. et al.: “Cytochrome P450 1B1 Val432Leu polymorphism and breast cancer risk in Nigerian women: a case control study”. Infect. Agent Cancer, 2009, 4 (suppl. 1), S12.

[11] Daayana S., Holland C.M.: “Hormone replacement therapy and the endometrium”. Menopause Int., 2009, 15, 134.

[12] Potischman N., Hoover R.N., Brinton L.A., Siiteri P., Dorgan J.F., Swanson C.A. et al.: “Case-control study of endogenous steroid hormones and endometrial cancer”. J. Natl. Cancer Inst., 1996, 88, 1127-35.

[13] Allen N.E., Key T.J., Dossus L., Rinaldi S., Cust A., Lukanova A. et al.: Endogenous sex hormones and endometrial cancer risk in women in the European Prospective Investigation into Cancer and Nutrition (EPIC)”. Endocr. Relat. Cancer, 2008, 15, 485.

[14] Tang Y.M., Wo Y.Y., Stewart J., Hawkins A.L., Griffin C.A., Sutter T. R., Greenlee W.F.: “Isolation and characterization of the human cytochrome P450 CYP1B1 gene”. J. Biol. Chem., 1996, 271, 28324.

[15] Lewis D.F., Gillam E.M., Everett S.A., Shimada T.: “Molecular modelling of human CYP1B1 substrate interactions and investiga-tion of allelic variant effects on metabolism”. Chem. Biol. Inter-act., 2003, 145, 281.

[16] Rylander T., Wedren S., Granath F.: “Cytochrome P4501B1 gene polymorphisms and postmenopausal breast cancer risk”. Carcino-genesis, 2003, 24, 1533.

[17] Zimarina T.C., Kristensen V.N., Imianitov E.N.: “Polymorphism of CYP1B1 and COMT in breast and endometrial cancer”. Mol. Biol., 2004, 38, 386.

[18] Doherty J.A., Weiss N.S., Freeman R.J., Dightman D.A., Thornton P.J., Houck J.R. et al.: “Genetic factors in catechol estrogen metabolism in relation to the risk of endometrial cancer”. Cancer Epidemiol. Biomarkers Prev., 2005, 14, 357.

[19] Sobti R.C., Onsory K., Al-Badran A.I., Kaur P., Watanabe M., Krishan A., Mohan H.: “CYP17, SRD5A2, CYP1B1, and CYP2D6 gene polymorphisms with prostate cancer risk in North Indian population”. DNA Cell. Biol., 2006, 25, 287.

[20] Cecchin E., Russo A., Campagnutta E., Martella L., Toffoli G.: “Lack of association of CYP1 B1*3 polymorphism and ovarian cancer in a Caucasian population”. Int. J. Biol. Markers, 2004, 19, 160.

[21] Huber A., Bentz E.K., Schneeberger C., Huber J.C., Hefler L., Tempfer C.: “Ten polymorphisms of estrogen-metabolizing genes and a family history of colon cancer-an association study of multiple gene-gene interactions”. J. Soc. Gynecol. Investig., 2005, 12, e51.

[22] Yao L., Fang F., Wu Q., Zhong Y., Yu L.: “No association between CYP1B1 Val432Leu polymorphism and breast cancer risk: a metaanalysis involving 40,303 subjects”. Breast Cancer Res. Treat., 2009.

[23] Sasaki M., Tanaka Y., Kaneuchi M., Sakuragi N., Dahiya R.: “CYP1B1 gene polymorphisms have higher risk for endometrial cancer, and positive correlations with estrogen receptor alpha and estrogen receptor beta expressions”. Cancer Res., 2003, 63, 3913.

[24] Hanna I.H., Dawling S., Roodi N., Guengerich F.P., Parl F.F.: “Cytochrome P450 1B1 (CYP1B1) pharmacogenetics: associationof polymorphisms with functional differences in estrogen hydroxylation activity”. Cancer Res., 2000, 60, 3440.

[25] Lee K.M., Abel J., Ko Y., Harth V., Park W.Y., Seo J.S. et al.: “Genetic polymorphisms of cytochrome P450 19 and 1B1, alcohol use, and breast cancer risk in Korean women”. Br. J. Cancer, 2003, 88, 675.

[26] Esinler I., Aktas D., Alikasifoglu M., Tuncbilek E., Ayhan A.: “CYP1A1 gene polymorphism and risk of endometrial hyperplasia and endometrial carcinoma”. Int. J. Gynecol. Cancer, 2006, 16, 1407.

[27] Mikhailova O.N., Gulyaeva L.F., Prudnikov A.V., Gerasimov A.V., Krasilnikov S.E.: “Estrogen-metabolizing gene polymorphisms in the assessment of female hormone-dependent cancer risk”. Pharmacogenomics J., 2006, 6, 189.