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Genetic polymorphisms of ESR1, ESR2, CYP17A1, and CYP19A1 and the risk of breast cancer: a case control study from North India

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Tumor Biology

Abstract

Estrogen is a key driver of breast cancer and genes involved in its signaling and biosynthesis are crucial in breast cancer progression. In this study, we investigated the role of estrogen signaling and synthesis related genes polymorphism in susceptibility to breast cancer risk in North India population in a case–control approach. We examined the association of single nucleotide polymorphism (SNP) in estrogen receptors, ESR1 (rs2234693) and ESR2 (rs2987983); estrogen biosynthesis enzymes, CYP17A1 (rs743572); and aromatase, CYP19A1 (rs700519) with breast cancer risk. Cases (n = 360) were matched to controls (n = 360) by age, sex, ethnicity, and geographical location. Results provided evidence that all the genetic variants were significantly associated with breast cancer risk among North Indian women. Furthermore, on performing stratified analysis between breast cancer risk and different clinicopathological characteristics, we observed strong associations for menopausal status, estrogen receptor (ER), progesterone receptor (PR), human epidermal growth factor receptor 2 (HER2) status, clinical stage, and histological grade. Our results suggest that these genes could be used as molecular markers to assess breast cancer susceptibility and predicting prognosis in North India population.

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References

  1. Jemal A, Bray F, Center MM, Ferlay J, Ward E, Forman D. Global cancer statistics. CA: Cancer J Clin. 2011;61(2):69–90. doi:10.3322/caac.20107.

    Google Scholar 

  2. Breast cancer in developing countries. Lancet. 2009;374(9701):1567. doi: 10.1016/S0140-6736(09)61930-9.

  3. Leong SP, Shen ZZ, Liu TJ, Agarwal G, Tajima T, Paik NS, et al. Is breast cancer the same disease in Asian and Western countries? World J Surg. 2010;34(10):2308–24. doi:10.1007/s00268-010-0683-1.

    Article  PubMed  PubMed Central  Google Scholar 

  4. Takiar R, Srivastav A. Time trend in breast and cervix cancer of women in India - (1990-2003). Asian Pac J Cancer Prev. 2008;9(4):777–80.

    PubMed  Google Scholar 

  5. Yeole BB. Trends in cancer incidence in female breast, cervix uteri, corpus uteri, and ovary in India. Asian Pac J Cancer Prev. 2008;9(1):119–22.

    PubMed  Google Scholar 

  6. Nandakumar A, Ramnath T, Chaturvedi M. The magnitude of cancer breast in India: a summary. Indian J Surg Oncol. 2010;1(1):8–9. doi:10.1007/s13193-010-0004-z.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Hankinson SE, Colditz GA, Willett WC. Towards an integrated model for breast cancer etiology: the lifelong interplay of genes, lifestyle, and hormones. Breast Cancer Res. 2004;6(5):213–8. doi:10.1186/bcr921 bcr921.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Key TJ, Verkasalo PK, Banks E. Epidemiology of breast cancer. Lancet Oncol. 2001;2(3):133–40. doi:10.1016/S1470-2045(00)00254-0.

    Article  CAS  PubMed  Google Scholar 

  9. Lamote I, Meyer E, Massart-Leen AM, Burvenich C. Sex steroids and growth factors in the regulation of mammary gland proliferation, differentiation, and involution. Steroids. 2004;69(3):145–59. doi:10.1016/j.steroids.2003.12.008.

    Article  CAS  PubMed  Google Scholar 

  10. Pelekanou V, Leclercq G. Recent insights into the effect of natural and environmental estrogens on mammary development and carcinogenesis. Int J Dev Biol. 2011;55(7–9):869–78. doi:10.1387/ijdb.113369vp.

    Article  PubMed  Google Scholar 

  11. Yager JD, Davidson NE. Estrogen carcinogenesis in breast cancer. N Engl J Med. 2006;354(3):270–82. doi:10.1056/NEJMra050776.

    Article  CAS  PubMed  Google Scholar 

  12. Paruthiyil S, Parmar H, Kerekatte V, Cunha GR, Firestone GL, Leitman DC. Estrogen receptor beta inhibits human breast cancer cell proliferation and tumor formation by causing a G2 cell cycle arrest. Cancer Res. 2004;64(1):423–8.

    Article  CAS  PubMed  Google Scholar 

  13. Strom A, Hartman J, Foster JS, Kietz S, Wimalasena J, Gustafsson JA. Estrogen receptor beta inhibits 17beta-estradiol-stimulated proliferation of the breast cancer cell line T47D. Proc Natl Acad Sci U S A. 2004;101(6):1566–71. doi:10.1073/pnas.0308319100 0308319100.

    Article  PubMed  PubMed Central  Google Scholar 

  14. Brentano ST, Picado-Leonard J, Mellon SH, Moore CC, Miller WL. Tissue-specific, cyclic adenosine 3′,5′-monophosphate-induced, and phorbol ester-repressed transcription from the human P450c17 promoter in mouse cells. Mol Endocrinol. 1990;4(12):1972–9.

    Article  CAS  PubMed  Google Scholar 

  15. Simpson ER, Mahendroo MS, Means GD, Kilgore MW, Hinshelwood MM, Graham-Lorence S, et al. Aromatase cytochrome P450, the enzyme responsible for estrogen biosynthesis. Endocr Rev. 1994;15(3):342–55.

    CAS  PubMed  Google Scholar 

  16. Simpson ER. Sources of estrogen and their importance. J Steroid Biochem Mol Biol. 2003;86(3–5):225–30.

    Article  CAS  PubMed  Google Scholar 

  17. Yue W, Wang JP, Hamilton CJ, Demers LM, Santen RJ. In situ aromatization enhances breast tumor estradiol levels and cellular proliferation. Cancer Res. 1998;58(5):927–32.

    CAS  PubMed  Google Scholar 

  18. Utsumi T, Harada N, Maruta M, Takagi Y. Presence of alternatively spliced transcripts of aromatase gene in human breast cancer. J Clin Endocrinol Metab. 1996;81(6):2344–9.

    CAS  PubMed  Google Scholar 

  19. Jordan VC, Brodie AM. Development and evolution of therapies targeted to the estrogen receptor for the treatment and prevention of breast cancer. Steroids. 2007;72(1):7–25. doi:10.1016/j.steroids.2006.10.009.

    Article  CAS  PubMed  Google Scholar 

  20. Chen YC, Hunter DJ. Molecular epidemiology of cancer. CA Cancer J Clin. 2005;55(1):45–54. quiz 7.

    Article  PubMed  Google Scholar 

  21. Cai Q, Shu XO, Jin F, Dai Q, Wen W, Cheng JR, et al. Genetic polymorphisms in the estrogen receptor alpha gene and risk of breast cancer: results from the Shanghai Breast Cancer Study. Cancer Epidemiol Biomarkers Prev. 2003;12(9):853–9.

    CAS  PubMed  Google Scholar 

  22. Shen Y, Li DK, Wu J, Zhang Z, Gao E. Joint effects of the CYP1A1 MspI, ERalpha PvuII, and ERalpha XbaI polymorphisms on the risk of breast cancer: results from a population-based case–control study in Shanghai. China Cancer Epidemiol Biomarkers Prev. 2006;15(2):342–7. doi:10.1158/1055-9965.EPI-05-0485.

    Article  CAS  PubMed  Google Scholar 

  23. Surekha D, Vishnupriya S, Rao DN, Sailaja K, Raghunadharao D. PvuII polymorphism of estrogen receptor-alpha gene in breast cancer. Indian J Hum Genet. 2007;13(3):97–101. doi:10.4103/0971-6866.38983.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Li N, Dong J, Hu Z, Shen H, Dai M. Potentially functional polymorphisms in ESR1 and breast cancer risk: a meta-analysis. Breast Cancer Res Treat. 2010;121(1):177–84. doi:10.1007/s10549-009-0532-9.

    Article  CAS  PubMed  Google Scholar 

  25. Zhang B, Beeghly-Fadiel A, Lu W, Cai Q, Xiang YB, Zheng Y, et al. Evaluation of functional genetic variants for breast cancer risk: results from the Shanghai breast cancer study. Am J Epidemiol. 2011;173(10):1159–70. doi:10.1093/aje/kwr004.

    Article  PubMed  PubMed Central  Google Scholar 

  26. Boyapati SM, Shu XO, Ruan ZX, Cai Q, Smith JR, Wen W, et al. Polymorphisms in ER-alpha gene interact with estrogen receptor status in breast cancer survival. Clin Cancer Res. 2005;11(3):1093–8.

    CAS  PubMed  Google Scholar 

  27. Wang J, Higuchi R, Modugno F, Li J, Umblas N, Lee J, et al. Estrogen receptor alpha haplotypes and breast cancer risk in older Caucasian women. Breast Cancer Res Treat. 2007;106(2):273–80. doi:10.1007/s10549-007-9497-8.

    Article  CAS  PubMed  Google Scholar 

  28. Gonzalez-Zuloeta Ladd AM, Vasquez AA, Rivadeneira F, Siemes C, Hofman A, Stricker BH, et al. Estrogen receptor alpha polymorphisms and postmenopausal breast cancer risk. Breast Cancer Res Treat. 2008;107(3):415–9. doi:10.1007/s10549-007-9562-3.

    Article  CAS  PubMed  Google Scholar 

  29. Sakoda LC, Blackston CR, Doherty JA, Ray RM, Lin MG, Gao DL, et al. Selected estrogen receptor 1 and androgen receptor gene polymorphisms in relation to risk of breast cancer and fibrocystic breast conditions among Chinese women. Cancer Epidemiol. 2011;35(1):48–55. doi:10.1016/j.canep.2010.08.005.

    Article  CAS  PubMed  Google Scholar 

  30. Treeck O, Elemenler E, Kriener C, Horn F, Springwald A, Hartmann A, et al. Polymorphisms in the promoter region of ESR2 gene and breast cancer susceptibility. J Steroid Biochem Mol Biol. 2009;114(3–5):207–11. doi:10.1016/j.jsbmb.2009.02.012.

    Article  CAS  PubMed  Google Scholar 

  31. Bergman-Jungestrom M, Gentile M, Lundin AC, Wingren S. Association between CYP17 gene polymorphism and risk of breast cancer in young women. Int J Cancer. 1999;84(4):350–3. doi:10.1002/(SICI)1097-0215(19990820)84:4<350::AID-IJC3>3.0.CO;2-L.

    Article  CAS  PubMed  Google Scholar 

  32. Feigelson HS, Coetzee GA, Kolonel LN, Ross RK, Henderson BE. A polymorphism in the CYP17 gene increases the risk of breast cancer. Cancer Res. 1997;57(6):1063–5.

    CAS  PubMed  Google Scholar 

  33. Feigelson HS, McKean-Cowdin R, Coetzee GA, Stram DO, Kolonel LN, Henderson BE. Building a multigenic model of breast cancer susceptibility: CYP17 and HSD17B1 are two important candidates. Cancer Res. 2001;61(2):785–9.

    CAS  PubMed  Google Scholar 

  34. 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(4):766–71. doi:10.1093/carcin/bgn042.

    Article  CAS  PubMed  Google Scholar 

  35. Chakraborty A, Murthy NS, Chintamani C, Bhatnagar D, Mohil RS, Sharma PC, et al. CYP17 gene polymorphism and its association with high-risk north Indian breast cancer patients. J Hum Genet. 2007;52(2):159–65. doi:10.1007/s10038-006-0095-0.

    Article  PubMed  Google Scholar 

  36. Helzlsouer KJ, Huang HY, Strickland PT, Hoffman S, Alberg AJ, Comstock GW, et al. Association between CYP17 polymorphisms and the development of breast cancer. Cancer Epidemiol Biomarkers Prev. 1998;7(10):945–9.

    CAS  PubMed  Google Scholar 

  37. Dunning AM, Healey CS, Pharoah PD, Foster NA, Lipscombe JM, Redman KL, et al. No association between a polymorphism in the steroid metabolism gene CYP17 and risk of breast cancer. Br J Cancer. 1998;77(11):2045–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Nedelcheva Kristensen V, Haraldsen EK, Anderson KB, Lonning PE, Erikstein B, Karesen R, et al. CYP17 and breast cancer risk: the polymorphism in the 5′ flanking area of the gene does not influence binding to Sp-1. Cancer Res. 1999;59(12):2825–8.

    CAS  PubMed  Google Scholar 

  39. Mitrunen K, Jourenkova N, Kataja V, Eskelinen M, Kosma VM, Benhamou S, et al. Steroid metabolism gene CYP17 polymorphism and the development of breast cancer. Cancer Epidemiol Biomarkers Prev. 2000;9(12):1343–8.

    CAS  PubMed  Google Scholar 

  40. Setiawan VW, Schumacher FR, Haiman CA, Stram DO, Albanes D, Altshuler D, et al. CYP17 genetic variation and risk of breast and prostate cancer from the National Cancer Institute Breast and Prostate Cancer Cohort Consortium (BPC3). Cancer Epidemiol Biomarkers Prev. 2007;16(11):2237–46. doi:10.1158/1055-9965.EPI-07-0589.

    Article  CAS  PubMed  Google Scholar 

  41. Miyoshi Y, Iwao K, Ikeda N, Egawa C, Noguchi S. Breast cancer risk associated with polymorphism in CYP19 in Japanese women. Int J Cancer. 2000;89(4):325–8. doi:10.1002/1097-0215(20000720)89:4<325::AID-IJC2>3.0.CO;2-3.

    Article  CAS  PubMed  Google Scholar 

  42. Lee KM, Abel J, Ko Y, Harth V, Park WY, Seo JS, et al. Genetic polymorphisms of cytochrome P450 19 and 1B1, alcohol use, and breast cancer risk in Korean women. Br J Cancer. 2003;88(5):675–8. doi:10.1038/sj.bjc.6600761.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Long JR, Kataoka N, Shu XO, Wen W, Gao YT, Cai Q, et al. Genetic polymorphisms of the CYP19A1 gene and breast cancer survival. Cancer Epidemiol Biomarkers Prev. 2006;15(11):2115–22. doi:10.1158/1055-9965.EPI-06-0464.

    Article  CAS  PubMed  Google Scholar 

  44. Cai Q, Kataoka N, Li C, Wen W, Smith JR, Gao YT, et al. Haplotype analyses of CYP19A1 gene variants and breast cancer risk: results from the Shanghai Breast Cancer Study. Cancer Epidemiol Biomarkers Prev. 2008;17(1):27–32. doi:10.1158/1055-9965.EPI-07-0688.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Fasching PA, Loehberg CR, Strissel PL, Lux MP, Bani MR, Schrauder M, et al. Single nucleotide polymorphisms of the aromatase gene (CYP19A1), HER2/neu status, and prognosis in breast cancer patients. Breast Cancer Res Treat. 2008;112(1):89–98. doi:10.1007/s10549-007-9822-2.

    Article  CAS  PubMed  Google Scholar 

  46. Taylor JG, Choi EH, Foster CB, Chanock SJ. Using genetic variation to study human disease. Trends Mol Med. 2001;7(11):507–12.

    Article  CAS  PubMed  Google Scholar 

  47. Ye S, Dhillon S, Ke X, Collins AR, Day IN. An efficient procedure for genotyping single nucleotide polymorphisms. Nucleic Acids Res. 2001;29(17):E88–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Yaich L, Dupont WD, Cavener DR, Parl FF. Analysis of the PvuII restriction fragment-length polymorphism and exon structure of the estrogen receptor gene in breast cancer and peripheral blood. Cancer Res. 1992;52(1):77–83.

    CAS  PubMed  Google Scholar 

  49. Andersen TI, Heimdal KR, Skrede M, Tveit K, Berg K, Borresen AL. Oestrogen receptor (ESR) polymorphisms and breast cancer susceptibility. Hum Genet. 1994;94(6):665–70.

    CAS  PubMed  Google Scholar 

  50. Herrington DM, Howard TD, Brosnihan KB, McDonnell DP, Li X, Hawkins GA, et al. Common estrogen receptor polymorphism augments effects of hormone replacement therapy on E-selectin but not C-reactive protein. Circulation. 2002;105(16):1879–82.

    Article  CAS  PubMed  Google Scholar 

  51. Schuit SC, de Jong FH, Stolk L, Koek WN, van Meurs JB, Schoofs MW, et al. Estrogen receptor alpha gene polymorphisms are associated with estradiol levels in postmenopausal women. Eur J Endocrinol. 2005;153(2):327–34. doi:10.1530/eje.1.01973.

    Article  CAS  PubMed  Google Scholar 

  52. Gonzalez-Mancha R, Galan JJ, Crespo C, Iglesias Perez L, Gonzalez-Perez A, Moron FJ, et al. Analysis of the ERalpha germline PvuII marker in breast cancer risk. Med Sci Monit. 2008;14(3):CR136–43.

    CAS  PubMed  Google Scholar 

  53. Li LC, Yeh CC, Nojima D, Dahiya R. Cloning and characterization of human estrogen receptor beta promoter. Biochem Biophys Res Commun. 2000;275(2):682–9. doi:10.1006/bbrc.2000.3363 S0006-291X(00)93363-1.

    Article  CAS  PubMed  Google Scholar 

  54. Thellenberg-Karlsson C, Lindstrom S, Malmer B, Wiklund F, Augustsson-Balter K, Adami HO, et al. Estrogen receptor beta polymorphism is associated with prostate cancer risk. Clin Cancer Res. 2006;12(6):1936–41. doi:10.1158/1078-0432.CCR-05-0269.

    Article  CAS  PubMed  Google Scholar 

  55. Passarelli MN, Phipps AI, Potter JD, Makar KW, Coghill AE, Wernli KJ, et al. Common single-nucleotide polymorphisms in the estrogen receptor beta promoter are associated with colorectal cancer survival in postmenopausal women. Cancer Res. 2013;73(2):767–75. doi:10.1158/0008-5472.CAN-12-2484.

    Article  CAS  PubMed  Google Scholar 

  56. Feigelson HS, Shames LS, Pike MC, Coetzee GA, Stanczyk FZ, Henderson BE. Cytochrome P450c17alpha gene (CYP17) polymorphism is associated with serum estrogen and progesterone concentrations. Cancer Res. 1998;58(4):585–7.

    CAS  PubMed  Google Scholar 

  57. Haiman CA, Hankinson SE, Spiegelman D, Colditz GA, Willett WC, Speizer FE, et al. The relationship between a polymorphism in CYP17 with plasma hormone levels and breast cancer. Cancer Res. 1999;59(5):1015–20.

    CAS  PubMed  Google Scholar 

  58. Miyoshi Y, Ando A, Ooka M, Shiba E, Taguchi T, Tamaki Y, et al. Association of CYP17 genetic polymorphism with intra-tumoral estradiol concentrations but not with CYP17 messenger RNA levels in breast cancer tissue. Cancer Lett. 2003;195(1):81–6.

    Article  CAS  PubMed  Google Scholar 

  59. Wang H, Li Q, Wang T, Yang G, Wang Y, Zhang X, et al. A common polymorphism in the human aromatase gene alters the risk for polycystic ovary syndrome and modifies aromatase activity in vitro. Mol Hum Reprod. 2011;17(6):386–91. doi:10.1093/molehr/gar007.

    Article  CAS  PubMed  Google Scholar 

  60. Haiman CA, Stram DO, Pike MC, Kolonel LN, Burtt NP, Altshuler D, et al. A comprehensive haplotype analysis of CYP19 and breast cancer risk: the Multiethnic Cohort. Hum Mol Genet. 2003;12(20):2679–92. doi:10.1093/hmg/ddg294 ddg294.

    Article  CAS  PubMed  Google Scholar 

  61. Brodie A. Aromatase inhibitors in breast cancer. Trends Endocrinol Metab. 2002;13(2):61–5.

    Article  CAS  PubMed  Google Scholar 

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Acknowledgments

The authors would like to thank all the participants for their support. SA Husain acknowledges the support provided by the University Grants Commission (UGC), Government of India, for research funds and S Chattopadhyay acknowledges the support of Council of Scientific and Industrial Research (CSIR), Government of India, for research fellowship.

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Authors and Affiliations

  1. Department of Biotechnology, Jamia Millia Islamia, New Delhi, 110025, India

    Shilpi Chattopadhyay, Sarah Siddiqui, Md. Salman Akhtar, Mohammad Zeeshan Najm & Syed Akhtar Husain

  2. Department of Surgical Oncology, All India Institute of Medical Sciences, New Delhi, 110029, India

    S. V. S. Deo & N. K. Shukla

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  1. Shilpi Chattopadhyay
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  2. Sarah Siddiqui
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  3. Md. Salman Akhtar
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Correspondence to Syed Akhtar Husain.

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Chattopadhyay, S., Siddiqui, S., Akhtar, M.S. et al. Genetic polymorphisms of ESR1, ESR2, CYP17A1, and CYP19A1 and the risk of breast cancer: a case control study from North India. Tumor Biol. 35, 4517–4527 (2014). https://doi.org/10.1007/s13277-013-1594-1

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