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Estrogen Receptor Alpha Polymorphisms and the Risk of Malignancies

  • Published:
Pathology & Oncology Research

Abstract

Estrogens represent risk factors for endocrine-related cancers and play also an important role in the development and progression of other malignancies. In order to analyze the associations between estrogen receptor gene alpha polymorphisms and cancers susceptibility, we genotyped six single nucleotide polymorphisms (SNPs) in 163 Caucasian cancer patients—103 breast cancers and 60 other malignancies (colorectal, bladder, hepatocellular carcinoma and acute myeloid leukemia)—and 114 healthy controls using hybridization probes. We performed Armitage`s association trend-test to evaluate the risk. Linkage disequilibrium (LD) was assessed for each pair of markers. The genotypes CC and CT of rs3798577 were significantly associated with the cancers risk (p-trend breast = 4 × 10-5; p-trend cancers = 1 × 10-5); in discrepancy with breast cancer where the C-allele represented the risk allele, for bladder, hepatocellular carcinomas and leukemia, the T allele seems to confer susceptibility. The minor G allele of rs1801132 was protective in our cases (p = 1 × 10-4); for rs2228480, the heterozygous frequency was higher for cancer groups (p = 0.03); the SNP pairs rs2228480&rs3798577 and rs2234693&rs9340799 were in low LD; the haplotypes T-A of rs2234693&rs9340799 and G-C of rs2228480&rs3798577 showed a trend to be higher represented in breast cancers; T allele of rs2234693 was higher expressed in breast, colon cancers and leukemia; rs2077647 was associated with colon (p = 0.008, C-risk allele) and bladder (p = 0.01, T-risk allele) cancers. We concluded that ESR1 polymorphisms may have distinct impact in carcinogenesis and further genotyping will establish whether these findings remain significant in larger cohorts.

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Abbreviations

AML:

acute myeloid leukemia

AR:

androgen receptor

CRC:

colorectal cancer

ERα:

estrogen receptor alpha

ERβ:

estrogen receptor beta

ESR1:

estrogen receptor alpha gene

HCC:

hepatocellular carcinoma

HRT:

hormone replacement therapy

HWE:

Hardy-Weinberg equilibrium

LD:

linkage disequilibrium

MMR genes:

mismatch repair genes

PCR:

polymerase chain reaction

SNP:

single nucleotide polymorphism

UTR:

untranslated region

References

  1. Dunning AM, Healey CS, Pharoah PD et al (1999) A systematic review of genetic polymorphisms and breast cancer risk. Cancer Epidemiol Biomarkers Prev 8:843–854

    CAS  PubMed  Google Scholar 

  2. Pharoah PD, Antoniou AC, Easton DF, Ponder BA (2008) Polygenes, risk prediction, and targeted prevention of breast cancer. N Engl J Med 358:2796–2803

    Article  CAS  PubMed  Google Scholar 

  3. Ripperger T, Gadzicki MA, Schlegelberger B (2009) Breast cancer susceptibility: current knowledge and implications for genetic counseling. Eu J Human Genetics 17:722–731

    Article  CAS  Google Scholar 

  4. Pharoah PD, Tyrer J, Dunning AM et al (2007) Association between common variation in 120 candidate genes and breast cancer risk. PLoS Genet 3:e42

    Article  PubMed  Google Scholar 

  5. Gold B, Kirchhoff T, Stefanov S et al (2008) Genome-wide association study provides evidence for a breast cancer risk locus at 6q22.33. PNAS 105:4340–4345

    Article  CAS  PubMed  Google Scholar 

  6. Easton DF, Pooley KA, Dunning AM et al (2007) Genome-wide association study identifies novel breast cancer susceptibility loci. Nature 447:1087–1093

    Article  CAS  PubMed  Google Scholar 

  7. Baynes C, Healey CS, Pooley CA et al (2007) Common variants in the ATM, BRCA1, BRCA2, CHEK2 and TP53 cancer susceptibility genes are unlike to increase breast cancer risk. Breast Cancer Res 9:R27

    Article  PubMed  Google Scholar 

  8. Gennari L, Merlotti D, De Paola V et al (2005) Estrogen receptor gene polymorphisms and the genetics of osteoporosis: a HuGE review. Am J Epidemiol 161:307–320

    Article  CAS  PubMed  Google Scholar 

  9. Deroo BJ, Korach KS (2006) Estrogen receptors and human disease. J Clin Invest 116:561–570

    Article  CAS  PubMed  Google Scholar 

  10. Breivik RA, Lothe GI, Meling TO et al (1997) Different genetic pathways to proximal and distal colorectal cancer influenced by sex-related factors. Int J Cancer 74:664–667

    Article  CAS  PubMed  Google Scholar 

  11. Martineti V, Silvestri S, Tonelli F, Brandi ML (2008) Control of colon cancer development and progression by selected estrogen receptor modulators. Expert Rev Endocrinol Metab 3:503–511

    Article  CAS  Google Scholar 

  12. Foley EF, Jazaeri AA, Shupnik MA et al (2000) Selective loss of estrogen receptor beta in malignant human colon. Cancer Res 60:245–248

    CAS  PubMed  Google Scholar 

  13. Kouzmenko AP, Takeyama K, Kawasaki Y et al (2008) Ligand-dependent interaction between estrogen receptor alpha and adenomatous polyposis coli. Genes To Cells 13:723–730

    Article  CAS  PubMed  Google Scholar 

  14. Slattery ML, Sweeney C, Murtaugh M et al (2005) Associations between ERalpha, ERbeta, and AR genotypes and colon and rectal cancer. Cancer Epidemiol Biomarkers Prev 14:2936–2942

    Article  CAS  PubMed  Google Scholar 

  15. Liu W, Konduri SD, Bansal S et al (2006) Estrogen receptor-alpha binds p53 tumor suppressor protein directly and represses its function. J Biol Chemistry 281:9837–9840

    Article  CAS  Google Scholar 

  16. Teng J, Wang ZY, Jarrard DF, Bjorling DE (2008) Roles of estrogen receptor α and β in modulating urothelial cell proliferation. Endocr Relat Canc 15:351–364

    Article  CAS  Google Scholar 

  17. Sun W, Zhong F, Zhi L et al (2009) Systematic-omics analysis of HBV-associated liver diseases. Cancer Lett 286:89–95

    Article  CAS  PubMed  Google Scholar 

  18. Deng G, Zhou G, Zhai Y et al (2004) Association of estrogen receptor Alpha polymorphisms with susceptibility to chronic hepatitis B virus infection. Hepatology 40:318–326

    Article  CAS  PubMed  Google Scholar 

  19. Zhai Y, Zhou G, Deng G et al (2006) Estrogen receptor alpha polymorphisms associated with susceptibility to hepatocellular carcinoma in hepatitis B virus carriers. Gastroenterology 130:2001–2009

    Article  CAS  PubMed  Google Scholar 

  20. Danel L, Cordier G, Revillard JP, Saez S (1982) Presence of estrogen binding sites and growth-stimulating effect of estradiol in the human myelogenous cell line HL60. Cancer Res 42:4701–4705

    CAS  PubMed  Google Scholar 

  21. Hatfill SJ, Brusnicky J, Fester E (1991) Immunocytochemical identification of nuclear estrogen-receptors in human acute myeloid leukemia. Leuk Res 15:315–320

    Article  CAS  PubMed  Google Scholar 

  22. Skibola CF, Bracci PM, Halperin E et al (2008) Polymorphisms in the estrogen receptor 1 and vitamin C and matrix metalloproteinase gene families are associated with susceptibility to lymphoma. PLoS 3:e2816

    Google Scholar 

  23. Yuan HY, Chiou JJ, Tseng WH et al (2006) FASTSNP: an always up-to-date and extendable service for SNP function analysis and prioritization. Nucleic Acids Res 34(Web Server issue):W635–641

    Article  CAS  PubMed  Google Scholar 

  24. Conde L, Vaquerizas JM, Dopazo H, et al (2006) PupaSuite: finding functional single nucleotide polymorphisms for large-scale genotyping purposes. Nucleic Acids Res 34(Web Server issue):W621-625 Available from http://bioinfo.cipf.es/pupasuite/

  25. Raymond M, Rousset F (1995) GENEPOP (version 1.2): population genetics software for exact tests and ecumenicism. J. Heredity, 86:248–249. http://genepop.curtin.edu.au/

  26. Gaunt TR, Rodriguez S, Day INM (2007) Cubic exact solutions for the estimation of pair-wise haplotype frequencies: implications for linkage disequilibrium analyses and a web tool 'CubeX'. BMC Bioinformatics 8:428–437. Available from http://www.oege.org/software/cubex/

  27. International HapMap Consortium, Frazer KA, Ballinger DG, Cox DR et al (2007) A second generation human haplotype map of over 3.1 million SNPs. Nature 449:851–861

    Article  CAS  PubMed  Google Scholar 

  28. Nilsson M, Dahlmann I, Jiao H et al (2007) Impact of estrogen receptor gene polymorphisms and mRNA levels on obesity and lipolysis—a cohort study. BMC Medical Genetics 8:73–85

    Article  PubMed  Google Scholar 

  29. Zofková I, Zajícková K, Hill M (2002) The estrogen receptor alpha gene determines serum androstenedione levels in postmenopausal women. Steroids 67:815–819

    Article  PubMed  Google Scholar 

  30. Herrington DM, Howard TD, Hawkins GA (2002) Estrogen-receptor polymorphism and effects of estrogen replacement therapy on high-density lipoprotein cholesterol in women with coronary disease. N Engl J Med 346:967–974

    Article  CAS  PubMed  Google Scholar 

  31. Long JR, Xu H, Zhao LJ et al (2005) The estrogen receptor α gene is linked and/or associated with age of menarche in different ethnic groups. J Med Genet 42:796–800

    Article  CAS  PubMed  Google Scholar 

  32. Speer G, Cseh K, Winkler G (2001) Estrogen and vitamin D receptor (VDR) genotypes and the expression of ErbB-2 and EGF receptor in human rectal cancers. Eur J Cancer 37:1463–1468

    Article  CAS  PubMed  Google Scholar 

  33. Notarnicola M, Gristina R, Messa C (2001) Estrogen receptors and microsatellite instability in colorectal carcinoma patients. Cancer Lett 168:65–70

    Article  CAS  PubMed  Google Scholar 

  34. Kadiyska T, Yakulov T, Kaneva R et al (2007) Vitamin D and estrogen receptor gene polymorphisms and the risk of colorectal cancer in Bulgaria. Int J Colorectal Dis 22:395–400

    Article  PubMed  Google Scholar 

  35. Zuppan PJ (1989) Polymorphisms at the estrogen receptor locus and linkage relationships on chromosome 6q. Cytogenet Cell Genet 51:1116–1120

    Google Scholar 

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

    CAS  PubMed  Google Scholar 

  37. Jakimiuk AJ, Nowicka M, Bogusiewicz M et al (2007) Prevalence of estrogen receptor α PvuII and XbaI polymorphism in population of Polish postmenopausal women. Folia Histochem et cytobiol 45:331–338

    CAS  Google Scholar 

  38. Boyapati SM, Shu XO, Ruan ZX et al (2005) Polymorphisms in ER-α gene interact with estrogen receptor status in breast cancer survival. Clin Cancer Res 11:1093–1098

    CAS  PubMed  Google Scholar 

  39. Moret-Onland CN, van Gils CH, Roest M et al (2005) The estrogen receptor α gene and breast cancer risk. Canc Causes Contr 16:1195–1202

    Article  Google Scholar 

  40. Gonzalez-Zuloeta Ladd AM, Vasquez AA, Rivadeneira F et al (2008) Estrogen receptor α polymorphisms and postmenopausal breast cancer risk. Breast Cancer Res Treat 107:415–419

    Article  CAS  PubMed  Google Scholar 

  41. Wedren S, Lovmar L, Humphreys K et al (2004) Estrogen receptor α gene haplotype and postmenopausal breast cancer risk: a case control study. Breast Cancer Res 6:R437–R449

    Article  CAS  PubMed  Google Scholar 

  42. Anderson TI, Heimdal KR, Skrede M et al (2004) Oestrogen receptor (ESR) polymorphisms and breast cancer susceptibility. Hum Genet 94:665–670

    Google Scholar 

  43. Shin A, Kang D, Nishio H et al (2003) Estrogen receptor alpha gene polymorphisms and breast cancer risk. Breast Cancer Res Treat 80:127–131

    Article  CAS  PubMed  Google Scholar 

  44. Cai Q, Shu XO, Jin F et al (2003) Genetic polymorphisms in the estrogen receptor alpha gene and risk of breast cancer: results from the Shanghai breast cancer study. Cancer Epidemiol Biomarkers Prev 12:853–859

    CAS  PubMed  Google Scholar 

  45. Tanaka Y, Sasaki M, Kaneuchi M et al (2003) Estrogen receptor alpha polymorphisms and renal cell carcinoma-a possible risk. Mol Cell Endocrinol 202:109–116

    CAS  PubMed  Google Scholar 

  46. Tapper W, Hammond V, Gerty S, Ennis S, Simmonds P, Collins A, the Prospective study of Outcomes in Sporadic versus Hereditary breast cancer (POSH) Steering Group and Diana Eccles (2008) The influence of genetic variation in 30 selected genes on the clinical characteristics of early onset breast cancer. Breast Cancer Res 10:R108–R118

    Article  PubMed  Google Scholar 

  47. Einarsdottir K, Darabi H, Li Y et al (2008) ESR1 and EGF genetic variation in relation to breast cancer risk and survival. Breast Cancer Res 10:R15–R24

    Article  PubMed  Google Scholar 

  48. Hsiao WC, Young KC, Lin SL, Lin PW (2004) Estrogen receptor–α polymorphism in Taiwanese clinical breast cancer population: a case-control study. Breast Cancer Res 6:180–186

    Article  Google Scholar 

  49. Iwase H, Kobayashi S (1997) Alterations and polymorphisms of the estrogen receptor gene in breast cancer. Breast Cancer 4:57–66

    Article  PubMed  Google Scholar 

  50. Roodi N, Bailey LR, Kao WY et al (1995) Estrogen receptor gene analysis in estrogen receptor-positive and receptor-negative primary breast cancer. J Natl Cancer Inst 87:446–451

    Article  CAS  PubMed  Google Scholar 

  51. Vasconcelos A, Medeiros R, Veiga I et al (2002) Analysis of estrogen receptor polymorphism in codon 325 by PCR-SSCP in breast cancer: association with lymph node metastasis. Breast J 8:226–229

    Article  CAS  PubMed  Google Scholar 

  52. Southey MC, Batten LE, McCredie MR et al (1998) Estrogen receptor polymorphism at codon 325 and risk of breast cancer in women before age forty. J Nat Cancer Inst 90:532–536

    Article  CAS  PubMed  Google Scholar 

  53. Gallichio L, Berndt S, McSorley MA et al (2006) Polymorphisms in estrogen-metabolizing and estrogen receptor genes and the risk of developing breast cancer among a cohort of women with benign breast disease. BMC Cancer 6:173–184

    Article  Google Scholar 

  54. Gold B, Kalush F, Bergeron J et al (2004) Estrogen receptor genotypes and haplotypes associated with breast cancer risk. Cancer Res 64:8891–8900

    Article  CAS  PubMed  Google Scholar 

  55. Wang J, Higuchi R, Modugno F et al (2007) Estrogen receptor alpha haplotypes and breast cancer risk in older Caucasian women. Breast Cancer Res and Treat 106:273–280

    Article  CAS  Google Scholar 

  56. Yang J, Singleton DW, Shaughnessy EA, Khan SA (2008) The F-domain of estrogen receptor-alpha inhibits ligand induced receptor dimerization. Mol Cell Endocrinol 295:94–100

    Article  CAS  PubMed  Google Scholar 

  57. Venables JP (2004) Aberrant and alternative splicing in cancer. Cancer Res 64:7647–7654

    Article  CAS  PubMed  Google Scholar 

  58. Lin S, Coutinho-Mansfield G, Wang D et al (2008) The splicing factor SC35 has an active role in transcriptional elongation. Nat Struct&Mol Biol 15:819–826

    Article  CAS  Google Scholar 

  59. Shi J, Hu Z, Pabon K, Scotto KW (2008) Caffeine regulates alternative splicing in a subset of cancer-associated genes: a role for SC35. Mol Cell Biol 28:883–895

    Article  CAS  PubMed  Google Scholar 

  60. Long JR, Zhao LJ, Liu PY et al (2004) Pattern of linkage disequilibrium and haplotype distribution in disease candidate genes. BMC Genetics 5:11–18

    Article  PubMed  Google Scholar 

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Acknowledgements

This paper was supported by the Romanian grant no. 98/2007 PNII/CAPACITATI. We declare that we have no conflict of interest.

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Authors and Affiliations

  1. Biochemistry Department, University of Medicine and Pharmacy “Victor Babes” Timisoara, Eftimie Murgu 2A, Timisoara, 300041, Romania

    Andrei Anghel, Diana Narita, Edward Seclaman & Liviu Tamas

  2. Epidemiology Department, University of Medicine and Pharmacy “Victor Babes” Timisoara, Eftimie Murgu 2A, Timisoara, 300041, Romania

    Emilian Popovici & Mariana Anghel

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  1. Andrei Anghel
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  2. Diana Narita
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Correspondence to Diana Narita.

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Anghel, A., Narita, D., Seclaman, E. et al. Estrogen Receptor Alpha Polymorphisms and the Risk of Malignancies. Pathol. Oncol. Res. 16, 485–496 (2010). https://doi.org/10.1007/s12253-010-9263-9

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  • DOI: https://doi.org/10.1007/s12253-010-9263-9

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