20May 2017

POLYMORPHISMS OF ESTROGEN BIOSYNTHESIS AND METABOLIZING GENES IN EGYPTIAN WOMEN WITH BREAST CANCER.

  • PH D candidate, Physiology, Zoology Department, Faculty of science, Mansoura University; Egypt.
  • Asst Professor, Molecular Biology, Genetics Unit, Mansoura University; Egypt.
  • Professor , Physiology, Zoology Department , Faculty of science , Mansoura University; Egypt.
  • Asst Professor, Department of General Surgery &Oncology , Faculty of Medicine, Mansoura University; Egypt.
  • Professor, Molecular Biology, Genetics Unit, Mansoura University; Egypt.
Crossref Cited-by Linking logo
  • Abstract
  • Keywords
  • References
  • Cite This Article as
  • Corresponding Author

Polymorphisms of genes responsible for biosynthesis and metabolism of estrogen including CYP and COMT groups might play a role in breast cancer. This study aims to investigate the association of CYP17 MspA1I, CYP1A1 MspI, CYP1B1 G>C, and COMT G>A polymorphisms with breast cancer in Egyptian women. Participants were in the form of 152 Egyptian women with cancer breast in addition to 100 healthy controls. They were subjected to DNA analysis using PCR-RFLP technique to characterize genetic polymorphisms of CYP17 MspA1I, CYP1A1 MspI, CYP1B1 G>C, and COMT G>A. Interestingly all these polymorphisms showed a positive association with cancer breast but in a variable degrees. Highest association was found withCYP1B1 C allele (p = 0.000, OR=10.26, 95% CI = 5.98 ? 17.8) followed by COMT A allele (p = 0.000, OR=6.66, 95% CI= 4.09 ? 10.9) then Cyp1A1 MspI C allele (p = 0.000, OR=4.46, 95% CI=2.68 -7.47) and lastly the CYP17 MspA1 C allele (p = 0.058, OR=1.46, 95% CI =1.0 ? 2.1). Regarding clinical presentation, COMT A allele carriage was significantly higher among cases with positive lymph nodes (p=0.02) and in pre-menopausal cases (p= 0.020) while CYP 17 MspA1I C allele carriage was significantly higher among cases with negative breast feeding (P= 0.043). We can come to a conclusion that rare alleles of estrogen biosynthesis and metabolizing genes particularly CYP1B1 G>C, and COMT G>A followed by CYP1A1 MspI, and CYP17 MspA1I are associated with breast cancer among Egyptian women.


  1. BalmukhanovTS ,Khanseitova AK, Nigmatova VG, Varchenko SP, Sh. Zh. Talaeva, Aitkhozhina NA . Associations of Polymorphisms of the CYP1A1 and CYP1B1 Cytochrome P450 Genes with Breast Cancer in Kazakhstan. Advances in Breast Cancer Research, 2013, 2, 51-55.
  2. Bozina N, Bradamante V, Lovric M: Genetic polymorphism of metabolic enzymes P450 (CYP) as a susceptibility factor for drug response, toxicity, and cancer risk. ArhHigRadaToksikol 2009; 60:217?242.
  3. Butterworth NJ, Dragunow M. Medial septal cholinergic neurons express c-Jun but do not undergo DNA fragmentation after fornix-fimbria transections. Brain Res Mol Brain Res 1996; 43: 1?12.
  4. Carey AH, Waterworth D, Patel K, White D, Little J, Novelli P et al. Polycystic ovaries and premature male pattern baldness are associated with one allele of the steroid metabolism gene CYP17. Hum Mol Genet 1994; 3:1873?1876.
  5. Cavalieri EL, Kumar S, Todorovic R, Higginbotham S, Badawi AF, Rogan EG. Imbalance of estrogen homeostasis in kidney and liver of hamsters treated with estradiol: implications for estrogen-induced initiation of renal tumors. Chem Res Toxicol 2001;14:1041-50.
  6. Cavalieri EL, Stack DE, Devanesan PD, Todorovic R, Dwivedy I, Higginbotham S, Johansson SL, Patil KD, Gross ML, Gooden JK, et al.: Molecular origin of cancer: catechol estrogen-3,4-quinones as endogenous tumor initiators. ProcNatlAcadSci USA 1997; 94(20):10937-10942.
  7. Cerne JZ, Pohar-Perme M, Novakovic S, Frkovic-Grazio S, Stegel V, Gersak K. Combined effect of CYP1B1, COMT, GSTP1, and MnSOD genotypes and risk of postmenopausal breast cancer. J GynecolOncol 2011; 22:110?119.
  8. Chakraborty A, Murthy NS, Chintamani C, Bhatnagar D, Mohil RS, Sharma PC, Saxena S. CYP17 gene polymorphism and its association with high-risk north Indian breast cancer patients. J Hum Genet 2007; 52:159?165.
  9. Chen Y, Gammon MD, Teitelbaum SL, Britton JA, Terry MB, Shantakumar S 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. 2008; 29:766?771.
  10. da Fonte de Amorim L, Rossini A, Mendonca G, Lotsch P, de Almeida Sim?o T, de Moura Gallo C, Pinto L. CYP1A1, GSTM1, and GSTT1 polymorphisms and breast cancer risk in Brazilian women. Cancer Lett 2002;181:179-86.
  11. Delort L, Satih S, Kwiatkowski F, Bignon YJ, Bernard-Gallon DJ. Evaluation of breast cancer risk in a multigenic model including low penetrance genes involved in xenobiotic and estrogen metabolisms. Nutr Cancer 2010; 62:243?251.
  12. Ding HX, Fu YY, Chen WX, Wang ZW. COMT Val158Met polymorphism and breast cancer risk: evidence from 26 case?control studies. Breast Cancer Res Treat 2010; 123:265?270.
  13. dos Santos RA, Teixeira AC, Mayorano MB, Carrara HH, de Andrade J, Takahashi CS: Variability in estrogen-metabolizing genes and their association with genomic instability in untreated breast cancer patients and healthy women. J Biomed Biotechnol??????? 2011; ??? 2011:571784. doi:10.1155/2011/571784. Epub 2011 Jun 14.
  14. Elatar I. Cancer registration, NCI Egypt 2001, Cairo, Egypt, National Cancer Institute,2002.
  15. Fan YS, Sasi R, Lee C, et al. Localization of the humanCYP17 gene to 10q24.3 by fluorescence insitu hybridization and simultaneous chromosome banding. Genomics, 1992; 14, 1110-1.
  16. Feigelson HS, Shames LS, Pike MC, Coetzee GA, StanczykFZ ,Henderson BE. Cytochrome P450c17alpha gene (CYP17) polymorphism is associated with serum estrogen and progesterone concentrations. Cancer Res 1998; 58:585?587.
  17. Fredslund SO, Bonefeld-Jorgensen EC: Breast cancer in the Arctic?changes over the past decades. Int J Circumpolar Health 2012; 71:19155.
  18. Ghisari M, Eiberg H, Manhai Long and Eva C Bonefeld-J?rgensen1* Polymorphisms in Phase I and Phase II genes and breast cancer risk and relations to persistent organic pollutant exposure: a case?control study in Inuit women. Environmental Health 2014; 13:19.
  19. He XF , Wei W , Li SX, Su J, Zhang Y, Ye H , Liu Y and Wang W. Association between the COMT Val158Met polymorphism and breast cancer risk: a meta-analysis of 30,199 cases and 38,922 controls. MolBiol Rep.?? 2012 Jun; 39(6):6811?23.
  20. Hosny G, Elkaffas SM. A prediction model for the incidence patterns of female breast cancers in Alexandria, Egypt. J Egypt Public Health Assoc. 2002; 77(3-4):329-45.
  21. Hosseini M, Houshmand M, Ebrahimi A. Breast cancer risk not only was not associated with CYP17 A2 allele but also was related to A1 allele. Arch Med Sci 2009; 5:103?106.
  22. Jiao H, Liu C, Guo W, Peng L, Chen Y and. Martin FL. Association of CYP1B1 Polymorphisms with Breast Cancer: A Case-Control Study in the Han Population in Ningxia Hui Autonomous Region, P. R. China Biomark Insights. 2010 Feb 12; 5 :21?27.
  23. Karakus N, Kara N, Ulusoy AN, Ozaslan C, Tural S, Okan I. Evaluation of CYP17A1 and LEP Gene Polymorphisms in Breast Cancer. Oncol Res Treat. 2015;38(9):418-22. doi: 10.1159/000438940. Epub 2015 Aug 18.
 
  1. Kato I, Cichon M, Yee CL, Land S, Korczak JF. African American-preponderant single nucleotide polymorphisms (SNPs) and risk of breast cancer. Cancer Epidemiol 2009; 33:24?30.
  2. Kawajiri K, Watanabe J, Gotoh O, et al. Structure and drug inducibility of the human cytochrome P-450c gene. Eur J Biochem 1986;159:219?25.
  3. Kristensen VN, Borresen-Dale AL. Molecular epidemiology of breast cancer: genetic variation in steroid hormone metabolism. Mutat Res 2000;462:323 ? 33.
  4. Lachman HM, Papolos DF, Saito T, Yu YM, Szumlanski CL, Weinshilboum RM. Human catechol-o-methyltransferasepharmacogenetics: description of a functional polymorphism and its potential application to neuropsychiatric disorders. Pharmacogenetics. 1996; 6:25?243.
  5. Lajin B, Hamzeh AR, Ghabreau L, Mohamed A, AlMoustafa AE, Alachkar A: Catechol-O-methyltransferase Val 108/158 Met polymorphism and breast cancer risk: a case control study in Syria. Breast cancer (Tokyo, Japan) 2011; Epub ahead of print.
  6. Law MR. Genetic predisposition to lung cancer. Br J Cancer 1990;61:195-206.
  7. Liehr JG, Fang WF, Sirbasku DA, Ari-Ulubelen A: Carcinogenicity of catechol estrogens in Syrian hamsters. J Steroid Biochem 1986, 24(1):353-356.
  8. MARIE-GENICA Consortium on Genetic Susceptibility for Menopausal Hormone Therapy Related Breast Cancer Risk. Genetic polymorphisms in phase I and phase II enzymes and breast cancer risk associated with menopausal hormone therapy in postmenopausal women. Breast Cancer Res Treat 2009; 119:463?474.
  9. Miller WL. Early steps in androgen biosynthesis: from cholesterol to DHEA. BaillieresClinEndocrinolMetab 1998; 12:67?81.
  10. Mitrunen K, Hirvonen A. Molecular epidemiology of sporadic breast cancer. The role of polymorphic genes involved in oestrogen biosynthesis and Mutat Res 2003;544:9 ? 41.
  11. Naushad SM, Reddy CA, Rupasree Y, Pavani A, Digumarti RR, Gottumukkala SR, Kuppusamy P, Kutala VK: Cross-talk between one-carbon metabolism and xenobiotic metabolism: implications on oxidative DNA damage and susceptibility to breast cancer. Cell BiochemBiophys. 2011, 61 (3): 715-723. 10.1007/s12013-011-9245-x.
  12. Ociepa-Zawal M, Rubiś B, Filas V, Bręborowicz J, Trzeciak WH. Studies on CYP1A1, CYP1B1 and CYP3A4 gene polymorphisms in breast cancer patients. Ginekol Pol. 2009 Nov; 80(11):819-23.
  13. Okobia MN, Bunker CH, Garte SJ, Zmuda JM, Ezeome ER, Anyanwu SN, Uche EE, Osime U, Ojukwu J, Kuller LH, Ferrell RE, Taioli E. Cytochrome P450 1B1 Val432Leu polymorphism and breast cancer risk in Nigerian women: a case control study. Infect Agent Cancer 2009; 4 (Suppl 1):S12.
  14. Oliveira CB, Cardoso-Filho C, Bossi LS, Louren?o GJ, Costa-Gurgel MS, Lima CS. Association of CYP1A1 A4889G and T6235C polymorphisms with the risk of sporadic breast cancer in Brazilian women. Clinics (Sao Paulo). 2015 Oct;70(10):680-5. doi: 10.6061/clinics/2015(10)04.
  15. Reding KW, Chen C, Lowe K, Doody DR, Carlson CS, Chen CT, et al. Estrogen-related genes and their contribution to racial differences in breast cancer risk. Cancer Causes Control 2012; 23(5): 671-681.
  16. Reding KW, Weiss NS, Chen C, Li CI, Carlson CS, Wilkerson HW, Farin FM, Thummel KE, Daling JR, Malone KE. Genetic polymorphisms in the catechol estrogen metabolism pathway and breast cancer risk. Cancer Epidemiol Biomarkers Prev. 2009; 18:1461?1467.
  17. Sangrajrang S, Sato Y, Sakamoto H, Ohnami S, Laird NM, Khuhaprema T, Brennan P, Boffetta P, Yoshida T. Genetic polymorphisms of estrogen metabolizing enzyme and breast cancer risk in Thai women. Int J Cancer 2009; 125:837?843.
  18. Sazci A, Ergul E, Utkan NZ, Canturk NZ, Kaya G. Catechol- O-methyltransferase Val 108/158 Met polymorphism in premenopausal breast cancer patients. Toxicology 2004; 204:197?202.
  19. Scanlon PD, Raymond FA, Weinshilboum RM. Catechol- O-methyltransferase: thermolabile enzyme in erythrocytes of subjects homozygous for allele for low activity. Science. 1979; 5:63?65.
  20. Sigurdson AJ, Bhatti P, Chang SC, Rajaraman P, Doody MM, Bowen L, Simon SL, Weinstock RM, Linet MS, Rosenstein M, Stovall M, Alexander BH, Preston DL, Struewing JP. Polymorphisms in estrogen biosynthesis and metabolism-related genes, ionizing radiation exposure, and risk of breast cancer among US radiologic technologists. Breast Cancer Res Treat 2009; 118:177?184.
  21. Silva SN, Cabral MN, Bezerra de Castro G, Pires M,? Azevedo AP,? Manita I, Pina JE, Rueff J? and? Gaspar J. Breast cancer risk and polymorphisms in genes involved in metabolism of estrogens (CYP17, HSD17?1, COMT and MnSOD): Possible protective role of MnSOD gene polymorphism Val/Ala and Ala/Ala in women that never breast fed Oncol Rep. 2006 oct; 16(4): 781-8.
  22. Sun MY, Du HY, Zhu AN , Liang HY, de Garibay GR, Li FX , Li M, and Xue-Xi Yang XX. Genetic Polymorphisms in Estrogen-Related Genes and the Risk of Breast Cancer among Han Chinese Women Int. J. Mol. Sci. 2015 Feb 13; 16(2): 4121-35; doi:10.3390/ijms16024121.
  23. Syamala VS, Syamala V, Sheeja VR, Kuttan R, Balakrishnan R, Ankathil R. Possible risk modification by polymorphisms of estrogen metabolizing genes in familial breast cancer susceptibility in an Indian population. Cancer Invest 2010; 28:304?311.
  24. Taioli E, Bradlow HL, Garbers SV, Sepkovic DW, Osborne MP, Trachman J, Ganguly S, Garte SJ. Role of estradiol metabolism and CYP1A1 polymorphisms in breast cancer risk. Cancer Detect Prev 1999; 23:232?237.
  25. Thompson PA, Shields PG, Freudenheim JL, Stone A, Vena JE, Marshall JR, Graham S, Laughlin R, Nemoto T, Kadlubar FF, Ambrosone CB . Genetic polymorphisms in catechol- O-methyltransferase, menopausal status, and breast cancer risk. Cancer Res 1998; 58:2107?2110
  26. Van Emburgh BO, Hu JJ, Levine EA, Mosley LJ, Perrier ND, Freimanis RI, Allen GO, Rubin P, Sherrill GB, Shaw CS, Carey LA, Sawyer LR, Miller MS. Polymorphisms in CYP1B1,GSTM1, GSTT1 and GSTP1, and susceptibility to breast cancer. Oncol Rep 2008; 19:1311?1321
  27. Wan GX1, Cao YW1, Li WQ1, Li YC1, Li F1The Catechol-O-Methyltransferase Val158Met Polymorphism Contributes to the Risk of Breast Cancer in the Chinese Population: An Updated Meta-Analysis. J Breast Cancer. 2014 Jun;17(2):149-56. doi: 10.4048/jbc.2014.17.2.149. Epub 2014 Jun 27.
  28. Wang Q, Wang YP, Li JY, Yuan P, Yang F, Li H. Polymorphic catechol-O-methyltransferase gene, soy isoflavone intake and breast cancer in postmenopausal women: a case? control study. Chin J Cancer 2010; 29:683?688.
  29. Wu AH, Tseng CC, Van Den Berg D, Yu MC. Tea intake, COMT genotype, and breast cancer in Asian?American women. Cancer Res 2003; 63:7526?7529.
  30. Yager D, Liehr JG. Molecular mechanisms of estrogen carcinogenesis. Annu Rev PharmacolToxicol 1996; 36:203?232.
  31. Yue W, YagerJD, WangJP, JupeER, SantenRJ. Estrogen receptor-dependent and independent mechanisms of breast cancer carcinogenesis. Steroids 78 (2013) 161?170.
  32. Zhang L, Gu L, Qian B, Hao X, Zhang W, Wei Q, Chen K. Association of genetic polymorphisms of ER-alpha and the estradiol-synthesizing enzyme genes CYP17 and CYP19 with breast cancer risk in Chinese women. Breast Cancer Res Treat 2009; 114:327?338.

[Wafaa Tolba, Rizk El Baz, Azza I Othman, Sameh Roshdy and Ahmad Settin. (2017); POLYMORPHISMS OF ESTROGEN BIOSYNTHESIS AND METABOLIZING GENES IN EGYPTIAN WOMEN WITH BREAST CANCER. Int. J. of Adv. Res. 5 (May). 453-464] (ISSN 2320-5407). www.journalijar.com


Wafaa Tolba
PH D candidate, Physiology, Zoology Department, Faculty of science, Mansoura University; Egypt

DOI:


Article DOI: 10.21474/IJAR01/4131      
DOI URL: http://dx.doi.org/10.21474/IJAR01/4131