Breast Cancer Research and Treatment

, Volume 167, Issue 3, pp 741–749 | Cite as

The effect of genetic variants on the relationship between statins and breast cancer in postmenopausal women in the Women’s Health Initiative observational study

  • Cathryn H. Bock
  • Allison M. Jay
  • Gregory Dyson
  • Jennifer L. Beebe-Dimmer
  • Michele L. Cote
  • Lifang Hou
  • Barbara V. Howard
  • Pinkal Desai
  • Kristen Purrington
  • Ross Prentice
  • Michael S. Simon



Statins have been postulated to have chemopreventive activity against breast cancer. We evaluated whether germline genetic polymorphisms modified the relationship between statins and breast cancer risk using data from the Women’s Health Initiative. We evaluated these interactions using both candidate gene and agnostic genome-wide approaches.


To identify candidate gene–statin interactions, we tested interactions between 22 SNPS in nine candidate genes implicated in the effect of statins on lipid metabolism in 1687 cases and 1687 controls. We then evaluated statin use interaction with the remaining 30,380 SNPs available in this sample from the CGEMS GWAS study.


After adjusting for multiple comparisons, no SNP interactions with statin usage and risk of breast cancer were statistically significant in either the candidate genes or genome-wide approaches.


We found no evidence of SNP interactions with statin usage for breast cancer risk in a population of 3374 individuals. These results suggest that genome-wide common genetic variants do not moderate the association between statin usage and breast cancer in the population of women in the Women’s Health Initiative.


GWAS Breast cancer SNPS Cholesterol Statins 



We thank Mary Pettinger at the WHI Clinical Coordinating Center for her help with the genotype data. The WHI program is funded by the National Heart, Lung, and Blood Institute, National Institutes of Health, U.S. Department of Health and Human Services through contracts HHSN268201100046C, HHSN268201100001C, HHSN268201100002C, HHSN268201100003C, HHSN268201100004C, and HHSN271201100004C. The WHI program is supported by contracts from the National Heart, Lung and Blood Institute, NIH. The authors thank the WHI investigators and staff for their dedication, and the study participants for making the program possible. A listing of WHI investigators can be found at

Compliance with ethical standards

Conflicts of interest

None of the authors has a conflict of interest.


  1. 1.
    Mann D, Reynolds K, Smith D, Muntner P (2008) Trends in statin use and low-density lipoprotein cholesterol levels among US adults: impact of the 2001 National Cholesterol Education Program guidelines. Ann Pharmacother 42(9):1208–1215CrossRefPubMedGoogle Scholar
  2. 2.
    Duncan RE, El-Sohemy A, Archer MC (2005) Statins and cancer development. Cancer Epidemiol Prev Biomark 14(8):1897–1898CrossRefGoogle Scholar
  3. 3.
    Liao JK (2002) Isoprenoids as mediators of the biological effects of statins. J Clin Investig 110(3):285–288CrossRefPubMedPubMedCentralGoogle Scholar
  4. 4.
    Agarwal B, Halmos B, Feoktistov AS, Protiva P, Ramey WG, Chen M, Pothoulakis C, Lamont JT, Holt PR (2002) Mechanism of lovastatin-induced apoptosis in intestinal epithelial cells. Carcinogenesis 23(3):521–528CrossRefPubMedGoogle Scholar
  5. 5.
    Yasuda Y, Shimizu M, Shirakami Y, Sakai H, Kubota M, Hata K, Hirose Y, Tsurumi H, Tanaka T, Moriwaki H (2010) Pitavastatin inhibits azoxymethane-induced colonic preneoplastic lesions in C57BL/KsJ-db/db obese mice. Cancer Sci 101(7):1701–1707CrossRefPubMedGoogle Scholar
  6. 6.
    Postmus I, Trompet S, Deshmukh HA, Barnes MR, Li X, Warren HR, Chasman DI, Zhou K, Arsenault BJ, Donnelly LA, Wiggins KL, Avery CL, Griffin P, Feng Q, Taylor KD, Li G, Evans DS, Smith AV, de Keyser CE, Johnson AD, de Craen AJ, Stott DJ, Buckley BM, Ford I, Westendorp RG, Slagboom PE, Sattar N, Munroe PB, Sever P, Poulter N, Stanton A, Shields DC, O’Brien E, Shaw-Hawkins S, Chen YD, Nickerson DA, Smith JD, Dube MP, Boekholdt SM, Hovingh GK, Kastelein JJ, McKeigue PM, Betteridge J, Neil A, Durrington PN, Doney A, Carr F, Morris A, McCarthy MI, Groop L, Ahlqvist E, Welcome Trust Case Control C, Bis JC, Rice K, Smith NL, Lumley T, Whitsel EA, Sturmer T, Boerwinkle E, Ngwa JS, O’Donnell CJ, Vasan RS, Wei WQ, Wilke RA, Liu CT, Sun F, Guo X, Heckbert SR, Post W, Sotoodehnia N, Arnold AM, Stafford JM, Ding J, Herrington DM, Kritchevsky SB, Eiriksdottir G, Launer LJ, Harris TB, Chu AY, Giulianini F, MacFadyen JG, Barratt BJ, Nyberg F, Stricker BH, Uitterlinden AG, Hofman A, Rivadeneira F, Emilsson V, Franco OH, Ridker PM, Gudnason V, Liu Y, Denny JC, Ballantyne CM, Rotter JI, Adrienne Cupples L, Psaty BM, Palmer CN, Tardif JC, Colhoun HM, Hitman G, Krauss RM, Wouter Jukema J, Caulfield MJ (2014) Pharmacogenetic meta-analysis of genome-wide association studies of LDL cholesterol response to statins. Nat commun 5:5068. doi: 10.1038/ncomms6068 CrossRefPubMedPubMedCentralGoogle Scholar
  7. 7.
    Iakoubova OA, Sabatine MS, Rowland CM, Tong CH, Catanese JJ, Ranade K, Simonsen KL, Kirchgessner TG, Cannon CP, Devlin JJ, Braunwald E (2008) Polymorphism in KIF6 gene and benefit from statins after acute coronary syndromes: results from the PROVE IT-TIMI 22 study. J Am Coll Cardiol 51(4):449–455CrossRefPubMedGoogle Scholar
  8. 8.
    Link E, Parish S, Armitage J, Bowman L, Heath S, Matsuda F, Gut I, Lathrop M, Collins R (2008) SLCO1B1 variants and statin-induced myopathy—a genomewide study. N Engl J Med 359(8):789–799CrossRefPubMedGoogle Scholar
  9. 9.
    Muck AO, Seeger H, Wallwiener D (2004) Inhibitory effect of statins on the proliferation of human breast cancer cells. Int J Clin Pharmacol Ther 42(12):695–700CrossRefPubMedGoogle Scholar
  10. 10.
    Campbell MJ, Esserman LJ, Zhou Y, Shoemaker M, Lobo M, Borman E, Baehner F, Kumar AS, Adduci K, Marx C, Petricoin EF, Liotta LA, Winters M, Benz S, Benz CC (2006) Breast cancer growth prevention by statins. Cancer Res 66(17):8707–8714CrossRefPubMedGoogle Scholar
  11. 11.
    Newman TB, Hulley SB (1996) Carcinogenicity of lipid-lowering drugs. JAMA 275(1):55–60CrossRefPubMedGoogle Scholar
  12. 12.
    Blais L, Desgagne A, LeLorier J (2000) 3-Hydroxy-3-methylglutaryl coenzyme A reductase inhibitors and the risk of cancer: a nested case–control study. Arch Intern Med 160(15):2363–2368CrossRefPubMedGoogle Scholar
  13. 13.
    Boudreau DM, Gardner JS, Malone KE, Heckbert SR, Blough DK, Daling JR (2004) The association between 3-hydroxy-3-methylglutaryl conenzyme a inhibitor use and breast carcinoma risk among postmenopausal women: a case–control study. Cancer 100(11):2308–2316CrossRefPubMedGoogle Scholar
  14. 14.
    Coogan PF, Rosenberg L, Strom BL (2007) Statin use and the risk of 10 cancers. Epidemiology 18(2):213–219CrossRefPubMedGoogle Scholar
  15. 15.
    Eliassen AH, Colditz GA, Rosner B, Willett WC, Hankinson SE (2005) Serum lipids, lipid-lowering drugs, and the risk of breast cancer. Arch Intern Med 165(19):2264–2271CrossRefPubMedGoogle Scholar
  16. 16.
    Friis S, Poulsen AH, Johnsen SP, McLaughlin JK, Fryzek JP, Dalton SO, Sorensen HT, Olsen JH (2005) Cancer risk among statin users: a population-based cohort study. Int J Cancer 114(4):643–647CrossRefPubMedGoogle Scholar
  17. 17.
    Graaf MR, Beiderbeck AB, Egberts AC, Richel DJ, Guchelaar HJ (2004) The risk of cancer in users of statins. J Clin Oncol 22(12):2388–2394CrossRefPubMedGoogle Scholar
  18. 18.
    Kaye JA, Jick H (2004) Statin use and cancer risk in the general practice research database. Br J Cancer 90(3):635–637CrossRefPubMedPubMedCentralGoogle Scholar
  19. 19.
    Kaye JA, Meier CR, Walker AM, Jick H (2002) Statin use, hyperlipidaemia, and the risk of breast cancer. Br J Cancer 86(9):1436–1439CrossRefPubMedPubMedCentralGoogle Scholar
  20. 20.
    Setoguchi S, Glynn RJ, Avorn J, Mogun H, Schneeweiss S (2007) Statins and the risk of lung, breast, and colorectal cancer in the elderly. Circulation 115(1):27–33CrossRefPubMedGoogle Scholar
  21. 21.
    Woditschka S, Habel LA, Udaltsova N, Friedman GD, Sieh W (2010) Lipophilic statin use and risk of breast cancer subtypes. Cancer Epidemiol Prev Biomark 19(10):2479–2487CrossRefGoogle Scholar
  22. 22.
    Beck P, Wysowski DK, Downey W, Butler-Jones D (2003) Statin use and the risk of breast cancer. J Clin Epidemiol 56(3):280–285CrossRefPubMedGoogle Scholar
  23. 23.
    Coogan PF, Rosenberg L, Palmer JR, Strom BL, Zauber AG, Shapiro S (2002) Statin use and the risk of breast and prostate cancer. Epidemiology 13(3):262–267CrossRefPubMedGoogle Scholar
  24. 24.
    Eaton M, Eklof J, Beal JR, Sahmoun AE (2009) Statins and breast cancer in postmenopausal women without hormone therapy. Anticancer Res 29:5143–5148PubMedGoogle Scholar
  25. 25.
    Goldstein MR, Mascitelli L, Pezzetta F (2010) Might the widespread use of statin drugs explain the increase in prevalence of breast carcinoma in situ? Med Hypotheses 74(3):613–614CrossRefPubMedGoogle Scholar
  26. 26.
    Sacks FM, Pfeffer MA, Moye LA, Rouleau JL, Rutherford JD, Cole TG, Brown L, Warnica JW, Arnold JM, Wun CC, Davis BR, Braunwald E (1996) The effect of pravastatin on coronary events after myocardial infarction in patients with average cholesterol levels. Cholesterol and recurrent events trial investigators. N Engl J Med 335(14):1001–1009CrossRefPubMedGoogle Scholar
  27. 27.
    Shepherd J, Blauw GJ, Murphy MB, Bollen EL, Buckley BM, Cobbe SM, Ford I, Gaw A, Hyland M, Jukema JW, Kamper AM, Macfarlane PW, Meinders AE, Norrie J, Packard CJ, Perry IJ, Stott DJ, Sweeney BJ, Twomey C, Westendorp RG (2002) Pravastatin in elderly individuals at risk of vascular disease (PROSPER): a randomised controlled trial. Lancet 360(9346):1623–1630CrossRefPubMedGoogle Scholar
  28. 28.
    Cauley JA, McTiernan A, Rodabough RJ, Lacroix A, Bauer DC, Margolis KL, Paskett ED, Vitolins MZ, Furberg CD, Chlebowski RT (2006) Statin use and breast cancer: prospective results from the Women’s Health Initiative. J Natl Cancer Inst 98(10):700–707CrossRefPubMedGoogle Scholar
  29. 29.
    Cauley JA, Zmuda JM, Lui LY, Hillier TA, Ness RB, Stone KL, Cummings SR, Bauer DC (2003) Lipid-lowering drug use and breast cancer in older women: a prospective study. J Womens Health (Larchmt) 12(8):749–756CrossRefGoogle Scholar
  30. 30.
    Haukka J, Sankila R, Klaukka T, Lonnqvist J, Niskanen L, Tanskanen A, Wahlbeck K, Tiihonen J (2010) Incidence of cancer and statin usage–record linkage study. Int J Cancer 126(1):279–284CrossRefPubMedGoogle Scholar
  31. 31.
    Heart Protection Study Collaborative G (2002) MRC/BHF heart protection study of cholesterol lowering with simvastatin in 20,536 high-risk individuals: a randomised placebo-controlled trial. Lancet 360(9326):7–22. doi: 10.1016/S0140-6736(02)09327-3 CrossRefGoogle Scholar
  32. 32.
    Pocobelli G, Newcomb PA, Trentham-Dietz A, Titus-Ernstoff L, Hampton JM, Egan KM (2008) Statin use and risk of breast cancer. Cancer 112(1):27–33CrossRefPubMedGoogle Scholar
  33. 33.
    Bonovas S, Filioussi K, Tsavaris N, Sitaras NM (2005) Use of statins and breast cancer: a meta-analysis of seven randomized clinical trials and nine observational studies. J Clin Oncol 23(34):8606–8612CrossRefPubMedGoogle Scholar
  34. 34.
    Baigent C, Keech A, Kearney PM, Blackwell L, Buck G, Pollicino C, Kirby A, Sourjina T, Peto R, Collins R, Simes R (2005) Efficacy and safety of cholesterol-lowering treatment: prospective meta-analysis of data from 90,056 participants in 14 randomised trials of statins. Lancet 366(9493):1267–1278CrossRefPubMedGoogle Scholar
  35. 35.
    Kathiresan S, Melander O, Anevski D, Guiducci C, Burtt NP, Roos C, Hirschhorn JN, Berglund G, Hedblad B, Groop L, Altshuler DM, Newton-Cheh C, Orho-Melander M (2008) Polymorphisms associated with cholesterol and risk of cardiovascular events. N Engl J Med 358(12):1240–1249CrossRefPubMedGoogle Scholar
  36. 36.
    Poduri A, Khullar M, Bahl A, Sehrawat BS, Sharma Y, Talwar KK (2010) Common variants of HMGCR, CETP, APOAI, ABCB1, CYP3A4, and CYP7A1 genes as predictors of lipid-lowering response to atorvastatin therapy. DNA Cell Biol 29(10):629–637CrossRefPubMedGoogle Scholar
  37. 37.
    Medina MW (2010) The relationship between HMGCR genetic variation, alternative splicing, and statin efficacy. Discov Med 9(49):495–499PubMedGoogle Scholar
  38. 38.
    Lipkin SM, Chao EC, Moreno V, Rozek LS, Rennert H, Pinchev M, Dizon D, Rennert G, Kopelovich L, Gruber SB (2010) Genetic variation in 3-hydroxy-3-methylglutaryl CoA reductase modifies the chemopreventive activity of statins for colorectal cancer. Cancer Prev Res (Phila) 3(5):597–603CrossRefGoogle Scholar
  39. 39.
    The Women’s Health Initiative Study Group (1998) Design of the Women’s Health Initiative clinical trial and observational study. Control Clin Trials 19(1):61–109CrossRefGoogle Scholar
  40. 40.
    Anderson GL, Manson J, Wallace R, Lund B, Hall D, Davis S, Shumaker S, Wang CY, Stein E, Prentice RL (2003) Implementation of the Women’s Health Initiative study design. Ann Epidemiol 13(9 Suppl):S5–S17CrossRefPubMedGoogle Scholar
  41. 41.
    Langer RD, White E, Lewis CE, Kotchen JM, Hendrix SL, Trevisan M (2003) The Women’s Health Initiative observational study: baseline characteristics of participants and reliability of baseline measures. Ann Epidemiol 13(9 Suppl):S107–S121CrossRefPubMedGoogle Scholar
  42. 42.
    Thomas G, Jacobs KB, Kraft P, Yeager M, Wacholder S, Cox DG, Hankinson SE, Hutchinson A, Wang Z, Yu K, Chatterjee N, Garcia-Closas M, Gonzalez-Bosquet J, Prokunina-Olsson L, Orr N, Willett WC, Colditz GA, Ziegler RG, Berg CD, Buys SS, McCarty CA, Feigelson HS, Calle EE, Thun MJ, Diver R, Prentice R, Jackson R, Kooperberg C, Chlebowski R, Lissowska J, Peplonska B, Brinton LA, Sigurdson A, Doody M, Bhatti P, Alexander BH, Buring J, Lee IM, Vatten LJ, Hveem K, Kumle M, Hayes RB, Tucker M, Gerhard DS, Fraumeni JF Jr, Hoover RN, Chanock SJ, Hunter DJ (2009) A multistage genome-wide association study in breast cancer identifies two new risk alleles at 1p11.2 and 14q24.1 (RAD51L1). Nat Genet 41(5):579–584. doi: 10.1038/ng.353 CrossRefPubMedPubMedCentralGoogle Scholar
  43. 43.
    Talmud PJ, Drenos F, Shah S, Shah T, Palmen J, Verzilli C, Gaunt TR, Pallas J, Lovering R, Li K, Casas JP, Sofat R, Kumari M, Rodriguez S, Johnson T, Newhouse SJ, Dominiczak A, Samani NJ, Caulfield M, Sever P, Stanton A, Shields DC, Padmanabhan S, Melander O, Hastie C, Delles C, Ebrahim S, Marmot MG, Smith GD, Lawlor DA, Munroe PB, Day IN, Kivimaki M, Whittaker J, Humphries SE, Hingorani AD, investigators A, investigators N, Consortium B (2009) Gene-centric association signals for lipids and apolipoproteins identified via the HumanCVD BeadChip. Am J Hum Genet 85(5):628–642. doi: 10.1016/j.ajhg.2009.10.014 CrossRefGoogle Scholar
  44. 44.
    Clendening JW, Pandyra A, Boutros PC, El GS, Khosravi F, Trentin GA, Martirosyan A, Hakem A, Hakem R, Jurisica I, Penn LZ (2010) Dysregulation of the mevalonate pathway promotes transformation. Proc Natl Acad Sci 107(34):15051–15056CrossRefPubMedPubMedCentralGoogle Scholar
  45. 45.
    Duncan RE, El-Sohemy A, Archer MC (2006) Statins and the risk of cancer. JAMA 295(23):2720–2722CrossRefPubMedGoogle Scholar
  46. 46.
    Hamelin BA, Turgeon J (1998) Hydrophilicity/lipophilicity: relevance for the pharmacology and clinical effects of HMG-CoA reductase inhibitors. Trends Pharmacol Sci 19(1):26–37CrossRefPubMedGoogle Scholar
  47. 47.
    Schachter M (2005) Chemical, pharmacokinetic and pharmacodynamic properties of statins: an update. Fundam Clin Pharmacol 19(1):117–125CrossRefPubMedGoogle Scholar
  48. 48.
    Kumar AS, Campbell M, Benz CC, Esserman LJ (2006) A call for clinical trials: lipophilic statins may prove effective in treatment and prevention of particular breast cancer subtypes. J Clin Oncol 24(13):2127–2128CrossRefPubMedGoogle Scholar
  49. 49.
    Boudreau DM, Yu O, Miglioretti DL, Buist DS, Heckbert SR, Daling JR (2007) Statin use and breast cancer risk in a large population-based setting. Cancer Epidemiol Prev Biomark 16(3):416–421CrossRefGoogle Scholar
  50. 50.
    Desai P, Chlebowski R, Cauley JA, Manson JE, Wu C, Martin LW, Jay A, Bock C, Cote M, Petrucelli N, Rosenberg CA, Peters U, Agalliu I, Budrys N, Abdul-Hussein M, Lane D, Luo J, Park HL, Thomas F, Wactawski-Wende J, Simon MS (2013) Prospective analysis of association between statin use and breast cancer risk in the Women’s Health Initiative. Cancer Epidemiol Prev Biomark 22(10):1868–1876. doi: 10.1158/1055-9965.EPI-13-0562 CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2017

Authors and Affiliations

  • Cathryn H. Bock
    • 1
  • Allison M. Jay
    • 2
  • Gregory Dyson
    • 1
  • Jennifer L. Beebe-Dimmer
    • 1
  • Michele L. Cote
    • 1
  • Lifang Hou
    • 3
  • Barbara V. Howard
    • 4
  • Pinkal Desai
    • 5
  • Kristen Purrington
    • 1
  • Ross Prentice
    • 6
  • Michael S. Simon
    • 1
  1. 1.Karmanos Cancer InstituteWayne State University School of MedicineDetroitUSA
  2. 2.St. John Health SystemVan Elslander Cancer CenterGrosse Pointe WoodsUSA
  3. 3.Department of Preventive Medicine and Robert H. Lurie Comprehensive Cancer Center, Feinberg School of MedicineNorthwestern UniversityChicagoUSA
  4. 4.Medstar Health Research Institute and Georgetown/Howard Universities Center for Clinical and Translational ScienceHyattsvilleUSA
  5. 5.Division of Hematology/OncologyWeill Cornell Medical CollegeNew YorkUSA
  6. 6.Fred Hutchinson Cancer Research CenterSeattleUSA

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