Significance of the Estrogen Hormone and Single Nucleotide Polymorphisms in the Progression of Breast Cancer among Female

Document Type : Review Article


1 Department of Immunology and Allergy, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran

2 Department of Pathological Analysis Techniques, Advanced Research Center, Al-Kut University College, Kut, Iraq

3 Molecular Medicine Department, Faculty of Medicine, Mashhad University of Medical Science, Mashhad, Iran


Breast cancer is one of the most frequent types of malignancies among women and is internationally recognized as the main reason for cancer-caused mortality. Most breast tumors are heterogeneous and genetically complicated due to the involvement of several genes. Therefore, it is clinically important to study genetic variants that increase the risk of breast cancer. It is identified that the presence of polymorphisms in genes encoding regulatory hormones is linked to a higher risk of breast cancer. Additionally, circulating estrogen levels are connected to aromatase (CYP19A1) genes, which is a recognized risk factor for breast cancer progression. In this paper, the authors present a review study on the effect of estrogen and its Single Nucleotide Polymorphisms (SNPs) in the occurrence of breast cancer. This review mainly aimed to find out the connection between CYP19A1 gene variations and the risk of breast cancer, as well as its clinical characteristics and prognosis. Due to the highly special activity of the CYP19A1 enzyme in steroid production, suppression of the targeted CYP19A1 is a focused medication for breast cancer patients, which has only minor adverse effects. Numerous clinical trials over the last decade have shown that Aromatase inhibitors (AIs) not only outperform tamoxifen in terms of effectiveness but also have a lower adverse effect profile.  The AI is now widely accepted as a routine therapy option for postmenopausal females with Estrogen receptor-positive (ER+) breast cancer. Furthermore, not only dysregulation of gene expression in different genes related to distinguished pathways, such as estrogen metabolism, is essential in the progression of breast cancer but also particular SNPs can play an essential role in particular genes, such as CYP19A1. Different studies have demonstrated that these SNPs can be located in different sites of these genes, which are collected in this review. In a nutshell, more specific clinical trials are required to demonstrate the precise meditative role of anti-estrogen drugs in the treatment of ER+ breast cancer patients. Furthermore, more genotype analyses are needed to confirm the role of SNPs in the progression of breast cancer.


Main Subjects

  1. McCullough LE, Santella RM, Cleveland RJ, Millikan RC, Olshan AF, North KE, et al. Polymorphisms in DNA repair genes, recreational physical activity and breast cancer risk. Int J Cancer. 2014;134(3):654-63.
  2. Enger SM, Ross RK, Henderson B, Bernstein L. Breastfeeding history, pregnancy experience and risk of breast cancer. Br J Cancer. 1997;76(1):118-23.
  3. Jemal A, Siegel R, Ward E, Hao Y, Xu J, Thun MJ. Cancer statistics, 2009. CA Cancer J Clin. 2009;59(4):225-49.
  4. Porter PL. Global trends in breast cancer incidence and mortality. Salud Publica Mex. 2009;51 Suppl 2:s141-6.
  5. Rheinbay E, Parasuraman P, Grimsby J, Tiao G, Engreitz JM, Kim J, et al. Recurrent and functional regulatory mutations in breast cancer. Nature. 2017;547(7661):55-60.
  6. Germain D. Estrogen carcinogenesis in breast cancer. Endocrinol Metab Clin North Am. 2011;40(3):473-84, vii.
  7. Wu MH, Chou YC, Yu JC, Yu CP, Wu CC, Chu CM, et al. Hormonal and body-size factors in relation to breast cancer risk: a prospective study of 11,889 women in a low-incidence area. Ann Epidemiol. 2006;16(3):223-9.
  8. Feigelson HS, Henderson BE. Estrogens and breast cancer. Carcinogenesis. 1996;17(11):2279-84.
  9. O'Neill JS, Miller WR. Aromatase activity in breast adipose tissue from women with benign and malignant breast diseases. Br J Cancer. 1987;56(5):601-4.
  10. Devilee P, Rookus MA. A tiny step closer to personalized risk prediction for breast cancer. N Engl J Med. 2010;362(11):1043-5.
  11. Ulaganathan VK, Sperl B, Rapp UR, Ullrich A. Germline variant FGFR4 p.G388R exposes a membrane-proximal STAT3 binding site. Nature. 2015;528(7583):570-4.
  12. Deng N, Zhou H, Fan H, Yuan Y. Single nucleotide polymorphisms and cancer susceptibility. Oncotarget. 2017;8(66):110635-49.
  13. Zhang L, Gu L, Qian B, Hao X, Zhang W, Wei Q, et al. 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(2):327-38.
  14. Pineda B, Garcia-Perez MA, Cano A, Lluch A, Eroles P. Associations between aromatase CYP19 rs10046 polymorphism and breast cancer risk: from a case-control to a meta-analysis of 20,098 subjects. PLoS One. 2013;8(1): 53902.
  15. Simpson ER, Clyne C, Rubin G, Boon WC, Robertson K, Britt K, et al. Aromatase--a brief overview. Annu Rev Physiol. 2002;64:93-127.
  16. Tsuchiya Y, Nakajima M, Yokoi T. Cytochrome P450-mediated metabolism of estrogens and its regulation in human. Cancer Lett. 2005;227(2):115-24.
  17. Lakhani NJ, Venitz J, Figg WD, Sparreboom A. Pharmacogenetics of estrogen metabolism and transport in relation to cancer. Curr Drug Metab. 2003;4(6):505-13.
  18. Raftogianis R, Creveling C, Weinshilboum R, Weisz J. Estrogen metabolism by conjugation. J Natl Cancer Inst Monogr. 2000(27):113-24.
  19. Nelson LR, Bulun SE. Estrogen production and action. J Am Acad Dermatol. 2001;45(3 Suppl):S116-24.
  20. Yue W, Wang JP, Li Y, Fan P, Liu G, Zhang N, et al. Effects of estrogen on breast cancer development: Role of estrogen receptor independent mechanisms. Int J Cancer. 2010;127(8):1748-57.
  21. Zumoff B. Does postmenopausal estrogen administration increase the risk of breast cancer? Contributions of animal, biochemical, and clinical investigative studies to a resolution of the controversy. Proc Soc Exp Biol Med. 1998;217(1):30-7.
  22. Clemons M, Goss P. Estrogen and the risk of breast cancer. N Engl J Med. 2001;344(4):276-85.
  23. Kaaks R, Rinaldi S, Key TJ, Berrino F, Peeters PH, Biessy C, et al. Postmenopausal serum androgens, oestrogens and breast cancer risk: the European prospective investigation into cancer and nutrition. Endocr Relat Cancer. 2005;12(4):1071-82.
  24. Preston-Martin S, Pike MC, Ross RK, Henderson BE. Epidemiologic evidence for the increased cell proliferation model of carcinogenesis. Environ Health Perspect. 1993;101 Suppl 5:137-8.
  25. Park SK, Yim D-s, Yoon K-s, Choi I-m, Choi J-y, Yoo K-y, et al. Combined effect of GSTM1, GSTT1, and COMT genotypes in individual. Breast Cancer Res Treat. 2004;88(1):55-62.
  26. Ritchie MD, Hahn LW, Roodi N, Bailey LR, Dupont WD, Parl FF, et al. Multifactor-dimensionality reduction reveals high-order interactions among estrogen-metabolism genes in sporadic breast cancer. Am J Hum Genet. 2001;69(1):138-47.
  27. Gaikwad NW, Yang L, Muti P, Meza JL, Pruthi S, Ingle JN, et al. The molecular etiology of breast cancer: evidence from biomarkers of risk. Int J Cancer. 2008;122(9):1949-57.
  28. Samavat H, Kurzer MS. Estrogen metabolism and breast cancer. Cancer Lett. 2015;356(2 Pt A):231-43.
  29. Stack DE, Byun J, Gross ML, Rogan EG, Cavalieri EL. Molecular characteristics of catechol estrogen quinones in reactions with deoxyribonucleosides. Chem Res Toxicol. 1996;9(5):851-9.
  30. Cavalieri EL, Rogan EG. Unbalanced metabolism of endogenous estrogens in the etiology and prevention of human cancer. J Steroid Biochem Mol Biol. 2011;125(3-5):169-80.
  31. Taioli E, Bradlow HL, Garbers SV, Sepkovic DW, Osborne MP, Trachman J, et al. Role of estradiol metabolism and CYP1A1 polymorphisms in breast cancer risk. Cancer Detect Prev. 1999;23(3):232-7.
  32. Chattopadhyay S, Siddiqui S, Akhtar MS, Najm MZ, Deo SV, Shukla NK, et al. Genetic polymorphisms of ESR1, ESR2, CYP17A1, and CYP19A1 and the risk of breast cancer: a case control study from North India. Tumour Biol. 2014;35(5):4517-27.
  33. Talbott KE, Gammon MD, Kibriya MG, Chen Y, Teitelbaum SL, Long CM, et al. A CYP19 (aromatase) polymorphism is associated with increased premenopausal breast cancer risk. Breast Cancer Res Treat. 2008;111(3):481-7.
  34. Lee AJ, Cai MX, Thomas PE, Conney AH, Zhu BT. Characterization of the oxidative metabolites of 17beta-estradiol and estrone formed by 15 selectively expressed human cytochrome p450 isoforms. Endocrinology. 2003;144(8):3382-98.
  35. Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell. 2011;144(5):646-74.
  36. Badawi AF, Cavalieri EL, Rogan EG. Role of human cytochrome P450 1A1, 1A2, 1B1, and 3A4 in the 2-, 4-, and 16alpha-hydroxylation of 17beta-estradiol. Metabolism. 2001;50(9):1001-3.
  37. Simpson ER, Davis SR. Minireview: aromatase and the regulation of estrogen biosynthesis--some new perspectives. Endocrinology. 2001;142(11):4589-94.
  38. Simpson E, Rubin G, Clyne C, Robertson K, O'Donnell L, Davis S, et al. Local estrogen biosynthesis in males and females. Endocr Relat Cancer. 1999;6(2):131-7.
  39. Sasano H, Harada N. Intratumoral aromatase in human breast, endometrial, and ovarian malignancies. Endocr Rev. 1998;19(5):593-607.
  40. Chen SA, Besman MJ, Sparkes RS, Zollman S, Klisak I, Mohandas T, et al. Human aromatase: cDNA cloning, Southern blot analysis, and assignment of the gene to chromosome 15. DNA. 1988;7(1):27-38.
  41. Shozu M, Zhao Y, Bulun SE, Simpson ER. Multiple splicing events involved in regulation of human aromatase expression by a novel promoter, I.6. Endocrinology. 1998;139(4):1610-7.
  42. McPhaul MJ, Herbst MA, Matsumine H, Young M, Lephart ED. Diverse mechanisms of control of aromatase gene expression. J Steroid Biochem Mol Biol. 1993;44(4):341-6.
  43. Xu Q, Liu JW, He CY, Sun LP, Gong YH, Jing JJ, et al. The interaction effects of pri-let-7a-1 rs10739971 with PGC and ERCC6 gene polymorphisms in gastric cancer and atrophic gastritis. PLoS One. 2014;9(2):e89203.
  44. Shin Y, Kim IJ, Kang HC, Park JH, Park HR, Park HW, et al. The E-cadherin -347G->GA promoter polymorphism and its effect on transcriptional regulation. Carcinogenesis. 2004;25(6):895-9.
  45. Fan H, Liu D, Qiu X, Qiao F, Wu Q, Su X, et al. A functional polymorphism in the DNA methyltransferase-3A promoter modifies the susceptibility in gastric cancer but not in esophageal carcinoma. BMC Med. 2010;8:12.
  46. Raghav D, Sharma V, Agarwal SM. Structural investigation of deleterious non-synonymous SNPs of EGFR gene. Interdiscip Sci. 2013;5(1):60-8.
  47. Al-Mukaynizi FB, Alanazi M, Al-Daihan S, Parine NR, Almadi M, Aljebreen A, et al. CYP19A1 gene polymorphism and colorectal cancer etiology in Saudi population: case-control study. Onco Targets Ther. 2017;10:4559-67.
  48. Robbez-Masson LJ, Bodor C, Jones JL, Hurst HC, Fitzgibbon J, Hart IR, et al. Functional analysis of a breast cancer-associated FGFR2 single nucleotide polymorphism using zinc finger mediated genome editing. PLoS One. 2013;8(11):e78839.
  49. Campbell TM, Castro MAA, de Santiago I, Fletcher MNC, Halim S, Prathalingam R, et al. FGFR2 risk SNPs confer breast cancer risk by augmenting oestrogen responsiveness. Carcinogenesis. 2016;37(8):741-50.
  50. Liotta LA. Cancer cell invasion and metastasis. Sci Am. 1992;266(2):54-9, 62-3.
  51. Healey CS, Dunning AM, Durocher F, Teare D, Pharoah PD, Luben RN, et al. Polymorphisms in the human aromatase cytochrome P450 gene (CYP19) and breast cancer risk. Carcinogenesis. 2000;21(2):189-93.
  52. Ma CX, Adjei AA, Salavaggione OE, Coronel J, Pelleymounter L, Wang L, et al. Human aromatase: gene resequencing and functional genomics. Cancer Res. 2005;65(23):11071-82.
  53. Siiteri PK. Adipose tissue as a source of hormones. Am J Clin Nutr. 1987;45(1 Suppl):277-82.
  54. Wang M, Chu H, Wang S, Wang M, Wang W, Han S, et al. Genetic variant in APE1 gene promoter contributes to cervical cancer risk. Am J Obstet Gynecol. 2013;209(4):360 e1-7.
  55. Ferraldeschi R, Arnedos M, Hadfield KD, A'Hern R, Drury S, Wardley A, et al. Polymorphisms of CYP19A1 and response to aromatase inhibitors in metastatic breast cancer patients. Breast Cancer Res Treat. 2012;133(3):1191-8.
  56. Li CI, Malone KE, Porter PL, Weiss NS, Tang MT, Cushing-Haugen KL, et al. Relationship between long durations and different regimens of hormone therapy and risk of breast cancer. J Am Med Assoc. 2003;289(24):3254-63.
  57. von Schoultz E, Rutqvist LE, Stockholm Breast Cancer Study G. Menopausal hormone therapy after breast cancer: the Stockholm randomized trial. J Natl Cancer Inst. 2005;97(7):533-5.
  58. Osborne CK. Tamoxifen in the treatment of breast cancer. N Engl J Med. 1998;339(22):1609-18.
  59. van Leeuwen FE, van den Belt-Dusebout AW, van Leeuwen FE, Benraadt J, Diepenhorst FW, van Tinteren H, et al. Risk of endometrial cancer after tamoxifen treatment of breast cancer. Lancet. 1994;343(8895):448-52.
  60. Shao W, Brown M. Advances in estrogen receptor biology: prospects for improvements in targeted breast cancer therapy. Breast Cancer Res. 2004;6(1):39-52.
  61. Dutta U, Pant K. Aromatase inhibitors: past, present and future in breast cancer therapy. Med Oncol. 2008;25(2):113-24.
  62. Gibson L, Lawrence D, Dawson C, Bliss J. Aromatase inhibitors for treatment of advanced breast cancer in postmenopausal women. Cochrane Database Syst Rev. 2009(4):CD003370.
  63. Garreau JR, Delamelena T, Walts D, Karamlou K, Johnson N. Side effects of aromatase inhibitors versus tamoxifen: the patients' perspective. Am J Surg. 2006;192(4):496-8.