Skip to main content

Advertisement

SpringerLink
Log in

Polymorphisms in the BRCA1 and ABCB1 genes modulate menopausal hormone therapy associated breast cancer risk in postmenopausal women

  • Epidemiology
  • Published:
Breast Cancer Research and Treatment Aims and scope Submit manuscript

Abstract

Menopausal hormone therapy (HT) is associated with an increased breast cancer risk among postmenopausal women. In this study, we investigated genetic effect modification of HT associated breast cancer risk in 3,149 postmenopausal breast cancer patients and 5,489 controls from the two German population-based case–control studies MARIE and GENICA. Twenty-eight polymorphisms of 14 candidate genes including two drug and hormone transporter genes (ABCB1/MDR1 and SHBG), four genes involved in cell cycle regulation (BRCA1, P21/CDKN1A, STK15/AURKA and TP53), six cytokine genes (IGFBP3, IL6, TGFB1, TNF, LTA and IGF1), and two cytokine receptor genes (EGFR and ERBB2) were genotyped using validated methods. Conditional logistic regression was used to assess multiplicative statistical interaction between polymorphisms and duration of estrogen–progestagen therapy and estrogen monotherapy use with regard to breast cancer risk assuming log-additive and co-dominant modes of inheritance. Women homozygous for the major ABCB1_rs2214102_G allele were found to be at a significantly increased breast cancer risk associated with combined estrogen–progestagen therapy [odds ratio (OR) = 1.17, 95% confidence interval (CI) = 1.12–1.23, P interaction = 0.022]. Additionally, risk associated with estrogen monotherapy was modified by BRCA1_rs799917. We observed a trend with increasing minor T alleles leading to the highest risk in homozygous carriers of the minor allele [OR (95% CI) = 1.17 (0.98–1.39), 1.06 (0.98–1.14), and 1.02 (0.94–1.11) for homozygous minor, heterozygous, and homozygous major allele carriers, respectively; P interaction = 0.032]. Our results suggest that genetic variants in ABCB1 and BRCA1 may modify the effect of HT on postmenopausal breast cancer risk.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Lo PK, Sukumar S (2008) Epigenomics and breast cancer. Pharmacogenomics 9:1879–1902

    Article  CAS  PubMed  Google Scholar 

  2. Lichtenstein P, Holm NV, Verkasalo PK, Iliadou A, Kaprio J, Koskenvuo M, Pukkala E, Skytthe A, Hemminki K (2000) Environmental and heritable factors in the causation of cancer—analyses of cohorts of twins from Sweden, Denmark, and Finland. N Engl J Med 343:78–85

    Article  CAS  PubMed  Google Scholar 

  3. Beral V (2003) Breast cancer and hormone-replacement therapy in the million women study. Lancet 362:419–427

    Article  CAS  PubMed  Google Scholar 

  4. Rossouw JE, Anderson GL, Prentice RL et al (2002) Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results from the women’s health initiative randomized controlled trial. JAMA 288:321–333

    Article  CAS  PubMed  Google Scholar 

  5. Flesch-Janys D, Slanger T, Mutschelknauss E, Kropp S, Obi N, Vettorazzi E, Braendle W, Bastert G, Hentschel S, Berger J, Chang-Claude J (2008) Risk of different histological types of postmenopausal breast cancer by type and regimen of menopausal hormone therapy. Int J Cancer 123:933–941

    Article  CAS  PubMed  Google Scholar 

  6. Newcomb PA, Titus-Ernstoff L, Egan KM, Trentham-Dietz A, Baron JA, Storer BE, Willett WC, Stampfer MJ (2002) Postmenopausal estrogen and progestin use in relation to breast cancer risk. Cancer Epidemiol Biomarkers Prev 11:593–600

    CAS  PubMed  Google Scholar 

  7. Ross RK, Paganini-Hill A, Wan PC, Pike MC (2000) Effect of hormone replacement therapy on breast cancer risk: estrogen versus estrogen plus progestin. J Natl Cancer Inst 92:328–332

    Article  CAS  PubMed  Google Scholar 

  8. Schairer C, Lubin J, Troisi R, Sturgeon S, Brinton L, Hoover R (2000) Menopausal estrogen and estrogen-progestin replacement therapy and breast cancer risk. JAMA 283:485–491

    Article  CAS  PubMed  Google Scholar 

  9. Seeger H, Mueck AO (2008) Are the progestins responsible for breast cancer risk during hormone therapy in the postmenopause? Experimental vs. clinical data. J Steroid Biochem Mol Biol 109:11–15

    Article  CAS  PubMed  Google Scholar 

  10. Eliassen AH, Missmer SA, Tworoger SS, Spiegelman D, Barbieri RL, Dowsett M, Hankinson SE (2006) Endogenous steroid hormone concentrations and risk of breast cancer among premenopausal women. J Natl Cancer Inst 98:1406–1415

    Article  CAS  PubMed  Google Scholar 

  11. Key T, Appleby P, Barnes I, Reeves G (2002) Endogenous sex hormones and breast cancer in postmenopausal women: reanalysis of nine prospective studies. J Natl Cancer Inst 94:606–616

    CAS  PubMed  Google Scholar 

  12. The MARIE-GENICA Consortium on Genetic Susceptibility for Menopausal Hormone Therapy Related Breast Cancer Risk (2009) 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. doi:10.1007/s10549-009-0407-0

  13. Brandt B, Hermann S, Straif K, Tidow N, Buerger H, Chang-Claude J (2004) Modification of breast cancer risk in young women by a polymorphic sequence in the egfr gene. Cancer Res 64:7–12

    Article  CAS  PubMed  Google Scholar 

  14. Cox A, Dunning AM, Garcia-Closas M et al (2007) A common coding variant in CASP8 is associated with breast cancer risk. Nat Genet 39:352–358

    Article  CAS  PubMed  Google Scholar 

  15. Cui Y, Shu XO, Cai Q, Jin F, Cheng JR, Cai H, Gao YT, Zheng W (2005) Association of breast cancer risk with a common functional polymorphism (Asp327Asn) in the sex hormone-binding globulin gene. Cancer Epidemiol Biomarkers Prev 14:1096–1101

    Article  CAS  PubMed  Google Scholar 

  16. Driver KE, Song H, Lesueur F, Ahmed S, Barbosa-Morais NL, Tyrer JP, Ponder BA, Easton DF, Pharoah PD, Dunning AM (2008) Association of single-nucleotide polymorphisms in the cell cycle genes with breast cancer in the British population. Carcinogenesis 29:333–341

    Article  CAS  PubMed  Google Scholar 

  17. Dunning AM, Ellis PD, McBride S et al (2003) A transforming growth factorbeta1 signal peptide variant increases secretion in vitro and is associated with increased incidence of invasive breast cancer. Cancer Res 63:2610–2615

    CAS  PubMed  Google Scholar 

  18. Ewart-Toland A, Dai Q, Gao YT et al (2005) Aurora-A/STK15 T+91A is a general low penetrance cancer susceptibility gene: a meta-analysis of multiple cancer types. Carcinogenesis 26:1368–1373

    Article  CAS  PubMed  Google Scholar 

  19. Gaudet MM, Egan KM, Lissowska J et al (2007) Genetic variation in tumor necrosis factor and lymphotoxin-alpha (TNF-LTA) and breast cancer risk. Hum Genet 121:483–490

    Article  CAS  PubMed  Google Scholar 

  20. Johnson N, Fletcher O, Palles C et al (2007) Counting potentially functional variants in BRCA1, BRCA2 and ATM predicts breast cancer susceptibility. Hum Mol Genet 16:1051–1057

    Article  CAS  PubMed  Google Scholar 

  21. Langerod A, Bukholm IR, Bregard A, Lonning PE, Andersen TI, Rognum TO, Meling GI, Lothe RA, Borresen-Dale AL (2002) The TP53 codon 72 polymorphism may affect the function of TP53 mutations in breast carcinomas but not in colorectal carcinomas. Cancer Epidemiol Biomarkers Prev 11:1684–1688

    CAS  PubMed  Google Scholar 

  22. Nelson SE, Gould MN, Hampton JM, Trentham-Dietz A (2005) A case–control study of the HER2 Ile655Val polymorphism in relation to risk of invasive breast cancer. Breast Cancer Res 7:R357–R364

    Article  CAS  PubMed  Google Scholar 

  23. Sjalander A, Birgander R, Hallmans G, Cajander S, Lenner P, Athlin L, Beckman G, Beckman L (1996) p53 polymorphisms and haplotypes in breast cancer. Carcinogenesis 17:1313–1316

    Article  CAS  PubMed  Google Scholar 

  24. Slattery ML, Curtin K, Baumgartner R, Sweeney C, Byers T, Giuliano AR, Baumgartner KB, Wolff RR (2007) IL6, aspirin, nonsteroidal anti-inflammatory drugs, and breast cancer risk in women living in the southwestern United States. Cancer Epidemiol Biomarkers Prev 16:747–755

    Article  CAS  PubMed  Google Scholar 

  25. Thompson DJ, Healey CS, Baynes C et al (2008) Identification of common variants in the SHBG gene affecting sex hormone-binding globulin levels and breast cancer risk in postmenopausal women. Cancer Epidemiol Biomarkers Prev 17:3490–3498

    Article  CAS  PubMed  Google Scholar 

  26. Turgut S, Yaren A, Kursunluoglu R, Turgut G (2007) MDR1 C3435T polymorphism in patients with breast cancer. Arch Med Res 38:539–544

    Article  CAS  PubMed  Google Scholar 

  27. Wen W, Gao YT, Shu XO, Yu H, Cai Q, Smith JR, Zheng W (2005) Insulin-like growth factor-I gene polymorphism and breast cancer risk in Chinese women. Int J Cancer 113:307–311

    Article  CAS  PubMed  Google Scholar 

  28. Xie D, Shu XO, Deng Z, Wen WQ, Creek KE, Dai Q, Gao YT, Jin F, Zheng W (2000) Population-based, case–control study of HER2 genetic polymorphism and breast cancer risk. J Natl Cancer Inst 92:412–417

    Article  CAS  PubMed  Google Scholar 

  29. Zubor P, Lasabova Z, Hatok J, Stanclova A, Danko J (2007) A polymorphism C3435T of the MDR-1 gene associated with smoking or high body mass index increases the risk of sporadic breast cancer in women. Oncol Rep 18:211–217

    CAS  PubMed  Google Scholar 

  30. Pesch B, Ko Y, Brauch H et al (2005) Factors modifying the association between hormone-replacement therapy and breast cancer risk. Eur J Epidemiol 20:699–711

    Article  PubMed  Google Scholar 

  31. Justenhoven C, Pierl CB, Haas S et al (2008) The CYP1B1_1358_GG genotype is associated with estrogen receptor-negative breast cancer. Breast Cancer Res Treat 111:171–177

    Article  CAS  PubMed  Google Scholar 

  32. Barrett JC, Fry B, Maller J, Daly MJ (2005) Haploview: analysis and visualization of LD and haplotype maps. Bioinformatics 21:263–265

    Article  CAS  PubMed  Google Scholar 

  33. Gabriel SB, Schaffner SF, Nguyen H et al (2002) The structure of haplotype blocks in the human genome. Science 296:2225–2229

    Article  CAS  PubMed  Google Scholar 

  34. Obreiter M, Fischer C, Chang-Claude J, Beckmann L (2005) SDMinP: a program to control the family wise error rate using step-down minP adjusted P-values. Bioinformatics 21:3183–3184

    Article  CAS  PubMed  Google Scholar 

  35. Ambudkar SV, Dey S, Hrycyna CA, Ramachandra M, Pastan I, Gottesman MM (1999) Biochemical, cellular, and pharmacological aspects of the multidrug transporter. Annu Rev Pharmacol Toxicol 39:361–398

    Article  CAS  PubMed  Google Scholar 

  36. Gottesman MM, Pastan I, Ambudkar SV (1996) P-glycoprotein and multidrug resistance. Curr Opin Genet Dev 6:610–617

    Article  CAS  PubMed  Google Scholar 

  37. Barnes KM, Dickstein B, Cutler GB Jr, Fojo T, Bates SE (1996) Steroid treatment, accumulation, and antagonism of P-glycoprotein in multidrug-resistant cells. Biochemistry 35:4820–4827

    Article  CAS  PubMed  Google Scholar 

  38. Kim WY, Benet LZ (2004) P-glycoprotein (P-gp/MDR1)-mediated efflux of sex-steroid hormones and modulation of P-gp expression in vitro. Pharm Res 21:1284–1293

    Article  CAS  PubMed  Google Scholar 

  39. Hamilton KO, Yazdanian MA, Audus KL (2001) Modulation of P-glycoprotein activity in Calu-3 cells using steroids and beta-ligands. Int J Pharm 228:171–179

    Article  CAS  PubMed  Google Scholar 

  40. Ichikawa-Haraguchi M, Sumizawa T, Yoshimura A, Furukawa T, Hiramoto S, Sugita M, Akiyama S (1993) Progesterone and its metabolites: the potent inhibitors of the transporting activity of P-glycoprotein in the adrenal gland. Biochim Biophys Acta 1158:201–208

    CAS  PubMed  Google Scholar 

  41. Brinkmann U, Eichelbaum M (2001) Polymorphisms in the ABC drug transporter gene MDR1. Pharmacogenomics J 1:59–64

    CAS  PubMed  Google Scholar 

  42. Gudmundsdottir K, Ashworth A (2006) The roles of BRCA1 and BRCA2 and associated proteins in the maintenance of genomic stability. Oncogene 25:5864–5874

    Article  CAS  PubMed  Google Scholar 

  43. Welcsh PL, King MC (2001) BRCA1 and BRCA2 and the genetics of breast and ovarian cancer. Hum Mol Genet 10:705–713

    Article  CAS  PubMed  Google Scholar 

  44. Yeh S, Hu YC, Rahman M, Lin HK, Hsu CL, Ting HJ, Kang HY, Chang C (2000) Increase of androgen-induced cell death and androgen receptor transactivation by BRCA1 in prostate cancer cells. Proc Natl Acad Sci U S A 97:11256–11261

    Article  CAS  PubMed  Google Scholar 

  45. Scully R, Chen J, Plug A, Xiao Y, Weaver D, Feunteun J, Ashley T, Livingston DM (1997) Association of BRCA1 with Rad51 in mitotic and meiotic cells. Cell 88:265–275

    Article  CAS  PubMed  Google Scholar 

  46. Tommasi S, Pilato B, Pinto R, Monaco A, Bruno M, Campana M, Digennaro M, Schittulli F, Lacalamita R, Paradiso A (2008) Molecular and in silico analysis of BRCA1 and BRCA2 variants. Mutat Res 644:64–70

    CAS  PubMed  Google Scholar 

  47. Schnyder S, Du NT, Le HB, Singh S, Loredo GA, Vaughan AT (2009) Estrogen treatment induces MLL aberrations in human lymphoblastoid cells. Leuk Res 33:1400–1404

    Google Scholar 

  48. Tsutsui T, Tamura Y, Yagi E, Barrett JC (2000) Involvement of genotoxic effects in the initiation of estrogen-induced cellular transformation: studies using Syrian hamster embryo cells treated with 17beta-estradiol and eight of its metabolites. Int J Cancer 86:8–14

    Article  CAS  PubMed  Google Scholar 

  49. Fan S, Wang J, Yuan R, Ma Y, Meng Q, Erdos MR, Pestell RG, Yuan F, Auborn KJ, Goldberg ID, Rosen EM (1999) BRCA1 inhibition of estrogen receptor signaling in transfected cells. Science 284:1354–1356

    Article  CAS  PubMed  Google Scholar 

  50. Fan S, Ma YX, Wang C et al (2001) Role of direct interaction in BRCA1 inhibition of estrogen receptor activity. Oncogene 20:77–87

    Article  CAS  PubMed  Google Scholar 

  51. Slattery ML, Sweeney C, Wolff R, Herrick J, Baumgartner K, Giuliano A, Byers T (2007) Genetic variation in IGF1, IGFBP3, IRS1, IRS2 and risk of breast cancer in women living in Southwestern United States. Breast Cancer Res Treat 104:197–209

    Article  CAS  PubMed  Google Scholar 

  52. Diergaarde B, Potter JD, Jupe ER, Manjeshwar S, Shimasaki CD, Pugh TW, DeFreese DC, Gramling BA, Evans I, White E (2008) Polymorphisms in genes involved in sex hormone metabolism, estrogen plus progestin hormone therapy use, and risk of postmenopausal breast cancer. Cancer Epidemiol Biomarkers Prev 17:1751–1759

    Article  CAS  PubMed  Google Scholar 

  53. Patel AV, Cheng I, Canzian F et al (2008) IGF-1, IGFBP-1, and IGFBP-3 polymorphisms predict circulating IGF levels but not breast cancer risk: findings from the Breast and Prostate Cancer Cohort Consortium (BPC3). PLoS ONE 3:e2578

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

We are indebted to all women participating in the MARIE and the GENICA breast cancer case–control studies. We gratefully acknowledge support by interviewers, the recruiting hospitals, and physicians of the study regions as well as their collaborating pathologists. We thank W. Höppner and colleagues from BioGlobe GmbH, Hamburg for the extensive and excellent genotyping work and S. Behrens, R. Birr, W. Busch, U. Eilber, B. Kaspereit, N. Knese, K. Smit, S. Brod, A. Seidel-Renkert, and M. Gilbert for their most valuable technical assistance. This work was funded by the Federal Ministry of Education and Research (BMBF) Germany grants 01KH0401, 01KH0402, 01KH0410, 01KH0411. The MARIE study was supported by the Deutsche Krebshilfe e.V., grant number 70-2892-BR I, the Deutsches Krebsforschungszentrum (DKFZ) and the Hamburg Cancer Society. The GENICA study was supported by the BMBF grants 01KW9975/5, 01KW9976/8, 01KW9977/0, 01KW0114, the Robert Bosch Foundation of Medical Research, Stuttgart, Department of Internal Medicine, Evangelische Kliniken Bonn gGmbH, Johanniter Krankenhaus, Bonn, Deutsches Krebsforschungszentrum (DKFZ), Heidelberg and BGFA—Research Institute of Occupational Medicine of the German Social Accident Insurance, Bochum, Germany.

Competing interests

The authors declare that they have no competing interests.

Author information

Authors and Affiliations

    Consortia

    The MARIE-GENICA Consortium on Genetic Susceptibility for Menopausal Hormone Therapy Related Breast Cancer Risk

    Additional information

    The members of the consortium are given in the Appendix.

    Electronic supplementary material

    Below is the link to the electronic supplementary material.

    (PDF 257 kb)

    Appendix

    Appendix

    Consortium members include:

    German Cancer Research Center (DKFZ), Heidelberg, Germany: Sascha Abbas, Lars Beckmann, Jenny Chang-Claude, Rebecca Hein, Silke Kropp, Margie Parthimos (Division of Cancer Epidemiology); Thomas Dünnebier, Ute Hamann (Research Group on Molecular Genetics of Breast Cancer); Benedikt Brors, Roland Eils, Marc Zapatka (Division of Theoretical Bioinformatics).

    Dr. Margarete Fischer-Bosch-Institute of Clinical Pharmacology (IKP), Stuttgart, and University of Tübingen, Germany: Hiltrud Brauch, Christina Justenhoven.

    University Medical Center Hamburg-Eppendorf, Hamburg, Germany: Dieter Flesch-Janys (Department of Medical Biometry and Epidemiology, Center for Experimental Medicine); Wilhelm Braendle (Department of Gynecological Endocrinology and Reproductive Medicine, Center for Gynaecology, Obstetrics and Paediatrics).

    BGFA—Research Institute of Occupational Medicine of the German Social Accident Insurance, Ruhr University Bochum (Bochum, Germany): Thomas Brüning, Beate Pesch, Anne Spickenheuer.

    Evangelische Kliniken Bonn gGmbH, Johanniter Krankenhaus, Bonn, Germany: Christian Baisch, Yon-Dschun Ko (Department of Internal Medicine).

    Congenics AG, Hamburg, Germany: Norbert Dahmen.

    The Writing Group included (in alphabetical order): Sascha Abbas, Hiltrud Brauch, Jenny Chang-Claude, Thomas Dünnebier, Dieter Flesch-Janys, Ute Hamann, Rebecca Hein, Christina Justenhoven, Ramona Salazar.

    Corresponding Author: Thomas Dünnebier, German Cancer Research Center (DKFZ), Molecular Genetics of Breast Cancer, Im Neuenheimer Feld 580, 69120 Heidelberg, Germany. Tel.: 0049/6221/42-4720. Fax: 0049/6221/42-4721. E-mail: t.duennebier@dkfz-heidelberg.de.

    Rights and permissions

    Reprints and permissions

    About this article

    Cite this article

    The MARIE-GENICA Consortium on Genetic Susceptibility for Menopausal Hormone Therapy Related Breast Cancer Risk. Polymorphisms in the BRCA1 and ABCB1 genes modulate menopausal hormone therapy associated breast cancer risk in postmenopausal women. Breast Cancer Res Treat 120, 727–736 (2010). https://doi.org/10.1007/s10549-009-0489-8

    Download citation

    • Received:

    • Accepted:

    • Published:

    • Issue Date:

    • DOI: https://doi.org/10.1007/s10549-009-0489-8

    Keywords

    Search

    Navigation