Breast Cancer Research and Treatment

, Volume 121, Issue 3, pp 693–702

A genetic variant in the pre-miR-27a oncogene is associated with a reduced familial breast cancer risk

  • Rongxi Yang
  • Bettina Schlehe
  • Kari Hemminki
  • Christian Sutter
  • Peter Bugert
  • Barbara Wappenschmidt
  • Juliane Volkmann
  • Raymonda Varon
  • Bernhard H. F. Weber
  • Dieter Niederacher
  • Norbert Arnold
  • Alfons Meindl
  • Claus R. Bartram
  • Rita K. Schmutzler
  • Barbara Burwinkel
Epidemiology

Abstract

MicroRNAs (miRNAs) regulate pathways involved in cell differentiation, proliferation, development, and apoptosis by degradation of target mRNAs and/or repression of their translation. Although the single nucleotide polymorphisms (SNPs) in miRNAs target sites have been studied, the effects of SNPs in miRNAs are largely unknown. In our study, we first systematically sequenced miRNA genes reported to be involved in breast cancer to identify/verify SNPs. We analyzed four SNPs, one located in the pre-miRNA and the other three located in miRNA flanking regions, for a putative association with breast cancer risk. The SNP rs895819, located in the terminal loop of pre-miRNA-27a, showed a protective effect. In a large familial breast cancer study cohort, the rare [G] allele of rs895819 was found to be less frequent in the cases than in the controls, indicating a reduced familial breast cancer risk ([G] vs. [A]: OR = 0.88, 95% CI 0.78–0.99, P = 0.0287). Furthermore, age stratification revealed that the protective effect was mainly observed in the age group < 50 years of age ([G] vs. [A]: OR = 0.83, 95% CI 0.70–0.98, P = 0.0314), whereas no significant effect was observed in the age group ≥ 50 years of age, indicating a possible hormone-related effect. It has been shown that artificial mutations in the terminal loop of miR-27a can block the maturation process of the miRNA. We hypothesize that the G-variant of rs895819 might impair the maturation of the oncogenic miR-27a and thus, is associated with familial breast cancer risk.

Keywords

Breast cancer risk MicroRNA SNP Case–control study 

References

  1. 1.
    Bartel DP (2004) MicroRNAs: genomics, biogenesis, mechanism, and function. Cell 116:281–297CrossRefPubMedGoogle Scholar
  2. 2.
    Ambros V (2004) The functions of animal microRNAs. Nature 431:350–355CrossRefPubMedGoogle Scholar
  3. 3.
    Lee Y, Jeon K, Lee JT, Kim S, Kim VN (2002) MicroRNA maturation: stepwise processing and subcellular localization. EMBO J 21:4663–4670CrossRefPubMedGoogle Scholar
  4. 4.
    Lee Y, Ahn C, Han J, Choi H, Kim J, Yim J, Lee J, Provost P, Radmark O, Kim S et al (2003) The nuclear RNase III Drosha initiates microRNA processing. Nature 425:415–419CrossRefPubMedGoogle Scholar
  5. 5.
    Lund E, Guttinger S, Calado A, Dahlberg JE, Kutay U (2004) Nuclear export of microRNA precursors. Science 303:95–98CrossRefPubMedGoogle Scholar
  6. 6.
    Hutvagner G, McLachlan J, Pasquinelli AE, Balint E, Tuschl T, Zamore PD (2001) A cellular function for the RNA-interference enzyme Dicer in the maturation of the let-7 small temporal RNA. Science 293:834–838CrossRefPubMedGoogle Scholar
  7. 7.
    Ketting RF, Fischer SE, Bernstein E, Sijen T, Hannon GJ, Plasterk RH (2001) Dicer functions in RNA interference and in synthesis of small RNA involved in developmental timing in C. elegans. Genes Dev 15:2654–2659CrossRefPubMedGoogle Scholar
  8. 8.
    Martinez J, Patkaniowska A, Urlaub H, Luhrmann R, Tuschl T (2002) Single-stranded antisense siRNAs guide target RNA cleavage in RNAi. Cell 110:563–574CrossRefPubMedGoogle Scholar
  9. 9.
    Schwarz DS, Hutvagner G, Haley B, Zamore PD (2002) Evidence that siRNAs function as guides, not primers, in the Drosophila and human RNAi pathways. Mol Cell 10:537–548CrossRefPubMedGoogle Scholar
  10. 10.
    Baltimore D, Boldin MP, O’Connell RM, Rao DS, Taganov KD (2008) MicroRNAs: new regulators of immune cell development and function. Nat Immunol 9:839–845CrossRefPubMedGoogle Scholar
  11. 11.
    Brennecke J, Hipfner DR, Stark A, Russell RB, Cohen SM (2003) Bantam encodes a developmentally regulated microRNA that controls cell proliferation and regulates the proapoptotic gene hid in Drosophila. Cell 113:25–36CrossRefPubMedGoogle Scholar
  12. 12.
    Chang TC, Wentzel EA, Kent OA, Ramachandran K, Mullendore M, Lee KH, Feldmann G, Yamakuchi M, Ferlito M, Lowenstein CJ et al (2007) Transactivation of miR-34a by p53 broadly influences gene expression and promotes apoptosis. Mol Cell 26:745–752CrossRefPubMedGoogle Scholar
  13. 13.
    Calin GA, Cimmino A, Fabbri M, Ferracin M, Wojcik SE, Shimizu M, Taccioli C, Zanesi N, Garzon R, Aqeilan RI et al (2008) MiR-15a and miR-16-1 cluster functions in human leukemia. Proc Natl Acad Sci USA 105:5166–5171CrossRefPubMedGoogle Scholar
  14. 14.
    Dews M, Homayouni A, Yu D, Murphy D, Sevignani C, Wentzel E, Furth EE, Lee WM, Enders GH, Mendell JT et al (2006) Augmentation of tumor angiogenesis by a Myc-activated microRNA cluster. Nat Genet 38:1060–1065CrossRefPubMedGoogle Scholar
  15. 15.
    Xiao C, Rajewsky K (2009) MicroRNA control in the immune system: basic principles. Cell 136:26–36CrossRefPubMedGoogle Scholar
  16. 16.
    Johnson SM, Grosshans H, Shingara J, Byrom M, Jarvis R, Cheng A, Labourier E, Reinert KL, Brown D, Slack FJ (2005) RAS is regulated by the let-7 microRNA family. Cell 120:635–647CrossRefPubMedGoogle Scholar
  17. 17.
    He L, Thomson JM, Hemann MT, Hernando-Monge E, Mu D, Goodson S, Powers S, Cordon-Cardo C, Lowe SW, Hannon GJ et al (2005) A microRNA polycistron as a potential human oncogene. Nature 435:828–833CrossRefPubMedGoogle Scholar
  18. 18.
    O’Donnell KA, Wentzel EA, Zeller KI, Dang CV, Mendell JT (2005) c-Myc-regulated microRNAs modulate E2F1 expression. Nature 435:839–843CrossRefPubMedGoogle Scholar
  19. 19.
    Esquela-Kerscher A, Slack FJ (2006) Oncomirs—microRNAs with a role in cancer. Nat Rev Cancer 6:259–269CrossRefPubMedGoogle Scholar
  20. 20.
    Calin GA, Croce CM (2006) MicroRNA signatures in human cancers. Nat Rev Cancer 6:857–866CrossRefPubMedGoogle Scholar
  21. 21.
    Lu J, Getz G, Miska EA, Alvarez-Saavedra E, Lamb J, Peck D, Sweet-Cordero A, Ebert BL, Mak RH, Ferrando AA et al (2005) MicroRNA expression profiles classify human cancers. Nature 435:834–838CrossRefPubMedGoogle Scholar
  22. 22.
    Parkin DM, Bray F, Ferlay J, Pisani P (2005) Global cancer statistics, 2002. CA Cancer J Clin 55:74–108CrossRefPubMedGoogle Scholar
  23. 23.
    Hopper JL (2001) Genetic epidemiology of female breast cancer. Semin Cancer Biol 11:367–374CrossRefPubMedGoogle Scholar
  24. 24.
    Narod SA (2002) Modifiers of risk of hereditary breast and ovarian cancer. Nat Rev Cancer 2:113–123CrossRefPubMedGoogle Scholar
  25. 25.
    Ponder BA (2001) Cancer genetics. Nature 411:336–341CrossRefPubMedGoogle Scholar
  26. 26.
    Pharoah PD, Antoniou A, Bobrow M, Zimmern RL, Easton DF, Ponder BA (2002) Polygenic susceptibility to breast cancer and implications for prevention. Nat Genet 31:33–36CrossRefPubMedGoogle Scholar
  27. 27.
    Tchatchou S, Jung A, Hemminki K, Sutter C, Wappenschmidt B, Bugert P, Weber BH, Niederacher D, Arnold N, Varon-Mateeva R et al (2009) A variant affecting a putative miRNA target site in estrogen receptor (ESR) 1 is associated with breast cancer risk in premenopausal women. Carcinogenesis 30:59–64CrossRefPubMedGoogle Scholar
  28. 28.
    Landi D, Gemignani F, Naccarati A, Pardini B, Vodicka P, Vodickova L, Novotny J, Forsti A, Hemminki K, Canzian F et al (2008) Polymorphisms within micro-RNA-binding sites and risk of sporadic colorectal cancer. Carcinogenesis 29:579–584CrossRefPubMedGoogle Scholar
  29. 29.
    Kapeller J, Houghton LA, Monnikes H, Walstab J, Moller D, Bonisch H, Burwinkel B, Autschbach F, Funke B, Lasitschka F et al (2008) First evidence for an association of a functional variant in the microRNA-510 target site of the serotonin receptor-type 3E gene with diarrhea predominant irritable bowel syndrome. Hum Mol Genet 17:2967–2977CrossRefPubMedGoogle Scholar
  30. 30.
    Tavazoie SF, Alarcon C, Oskarsson T, Padua D, Wang Q, Bos PD, Gerald WL, Massague J (2008) Endogenous human microRNAs that suppress breast cancer metastasis. Nature 451:147–152CrossRefPubMedGoogle Scholar
  31. 31.
    Ma L, Teruya-Feldstein J, Weinberg RA (2007) Tumour invasion and metastasis initiated by microRNA-10b in breast cancer. Nature 449:682–688CrossRefPubMedGoogle Scholar
  32. 32.
    Yu F, Yao H, Zhu P, Zhang X, Pan Q, Gong C, Huang Y, Hu X, Su F, Lieberman J et al (2007) let-7 regulates self renewal and tumorigenicity of breast cancer cells. Cell 131:1109–1123CrossRefPubMedGoogle Scholar
  33. 33.
    Huang Q, Gumireddy K, Schrier M, le Sage C, Nagel R, Nair S, Egan DA, Li A, Huang G, Klein-Szanto AJ et al (2008) The microRNAs miR-373 and miR-520c promote tumour invasion and metastasis. Nat Cell Biol 10:202–210CrossRefPubMedGoogle Scholar
  34. 34.
    Lu L, Katsaros D, de la Longrais IA, Sochirca O, Yu H (2007) Hypermethylation of let-7a-3 in epithelial ovarian cancer is associated with low insulin-like growth factor-II expression and favorable prognosis. Cancer Res 67:10117–10122CrossRefPubMedGoogle Scholar
  35. 35.
    Sempere LF, Christensen M, Silahtaroglu A, Bak M, Heath CV, Schwartz G, Wells W, Kauppinen S, Cole CN (2007) Altered microRNA expression confined to specific epithelial cell subpopulations in breast cancer. Cancer Res 67:11612–11620CrossRefPubMedGoogle Scholar
  36. 36.
    Mertens-Talcott SU, Chintharlapalli S, Li X, Safe S (2007) The oncogenic microRNA-27a targets genes that regulate specificity protein transcription factors and the G2-M checkpoint in MDA-MB-231 breast cancer cells. Cancer Res 67:11001–11011CrossRefPubMedGoogle Scholar
  37. 37.
    Frankel LB, Christoffersen NR, Jacobsen A, Lindow M, Krogh A, Lund AH (2008) Programmed cell death 4 (PDCD4) is an important functional target of the microRNA miR-21 in breast cancer cells. J Biol Chem 283:1026–1033CrossRefPubMedGoogle Scholar
  38. 38.
    Meindl A (2002) Comprehensive analysis of 989 patients with breast or ovarian cancer provides BRCA1 and BRCA2 mutation profiles and frequencies for the German population. Int J Cancer 97:472–480CrossRefPubMedGoogle Scholar
  39. 39.
    Dupont WD, Plummer WD Jr (1998) Power and sample size calculations for studies involving linear regression. Control Clin Trials 19:589–601CrossRefPubMedGoogle Scholar
  40. 40.
    Zhang B, Pan X, Cobb GP, Anderson TA (2007) MicroRNAs as oncogenes and tumor suppressors. Dev Biol 302:1–12CrossRefPubMedGoogle Scholar
  41. 41.
    Osaki M, Takeshita F, Ochiya T (2008) MicroRNAs as biomarkers and therapeutic drugs in human cancer. Biomarkers 13:658–670CrossRefPubMedGoogle Scholar
  42. 42.
    Verghese ET, Hanby AM, Speirs V, Hughes TA (2008) Small is beautiful: microRNAs and breast cancer-where are we now? J Pathol 215:214–221CrossRefPubMedGoogle Scholar
  43. 43.
    Wu M, Jolicoeur N, Li Z, Zhang L, Fortin Y, L’Abbe D, Yu Z, Shen SH (2008) Genetic variations of microRNAs in human cancer and their effects on the expression of miRNAs. Carcinogenesis 29:1710–1716CrossRefPubMedGoogle Scholar
  44. 44.
    Houlston RS, Peto J (2003) The future of association studies of common cancers. Hum Genet 112:434–435PubMedGoogle Scholar
  45. 45.
    Antoniou AC, Easton DF (2003) Polygenic inheritance of breast cancer: implications for design of association studies. Genet Epidemiol 25:190–202CrossRefPubMedGoogle Scholar
  46. 46.
    Weitzel JN, Robson M, Pasini B, Manoukian S, Stoppa-Lyonnet D, Lynch HT, McLennan J, Foulkes WD, Wagner T, Tung N et al (2005) A comparison of bilateral breast cancers in BRCA carriers. Cancer Epidemiol Biomark Prev 14:1534–1538CrossRefGoogle Scholar
  47. 47.
    Greene MH (1997) Genetics of breast cancer. Mayo Clin Proc 72:54–65CrossRefPubMedGoogle Scholar
  48. 48.
    Markham NR, Zuker M (2005) DINAMelt web server for nucleic acid melting prediction. Nucleic Acids Res 33:W577–W581CrossRefPubMedGoogle Scholar
  49. 49.
    Jazdzewski K, Murray EL, Franssila K, Jarzab B, Schoenberg DR, de la Chapelle A (2008) Common SNP in pre-miR-146a decreases mature miR expression and predisposes to papillary thyroid carcinoma. Proc Natl Acad Sci USA 105:7269–7274CrossRefPubMedGoogle Scholar
  50. 50.
    Hu Z, Chen J, Tian T, Zhou X, Gu H, Xu L, Zeng Y, Miao R, Jin G, Ma H et al (2008) Genetic variants of miRNA sequences and non-small cell lung cancer survival. J Clin Investig 118:2600–2608CrossRefPubMedGoogle Scholar
  51. 51.
    Duan R, Pak C, Jin P (2007) Single nucleotide polymorphism associated with mature miR-125a alters the processing of pri-miRNA. Hum Mol Genet 16:1124–1131CrossRefPubMedGoogle Scholar
  52. 52.
    Zeng Y, Yi R, Cullen BR (2005) Recognition and cleavage of primary microRNA precursors by the nuclear processing enzyme Drosha. EMBO J 24:138–148CrossRefPubMedGoogle Scholar
  53. 53.
    Piskounova E, Viswanathan SR, Janas M, LaPierre RJ, Daley GQ, Sliz P, Gregory RI (2008) Determinants of microRNA processing inhibition by the developmentally regulated RNA-binding protein Lin28. J Biol Chem 283:21310–21314CrossRefPubMedGoogle Scholar
  54. 54.
    Newman MA, Thomson JM, Hammond SM (2008) Lin-28 interaction with the Let-7 precursor loop mediates regulated microRNA processing. RNA 14:1539–1549CrossRefPubMedGoogle Scholar
  55. 55.
    Sun T, Gao Y, Tan W, Ma S, Shi Y, Yao J, Guo Y, Yang M, Zhang X, Zhang Q et al (2007) A six-nucleotide insertion-deletion polymorphism in the CASP8 promoter is associated with susceptibility to multiple cancers. Nat Genet 39:605–613CrossRefPubMedGoogle Scholar
  56. 56.
    Scott GK, Mattie MD, Berger CE, Benz SC, Benz CC (2006) Rapid alteration of microRNA levels by histone deacetylase inhibition. Cancer Res 66:1277–1281CrossRefPubMedGoogle Scholar
  57. 57.
    Liu T, Tang H, Lang Y, Liu M, Li X (2009) MicroRNA-27a functions as an oncogene in gastric adenocarcinoma by targeting prohibitin. Cancer Lett 273:233–242CrossRefPubMedGoogle Scholar
  58. 58.
    Ji J, Zhang J, Huang G, Qian J, Wang X, Mei S (2009) Over-expressed microRNA-27a and 27b influence fat accumulation and cell proliferation during rat hepatic stellate cell activation. FEBS Lett 583:759–766CrossRefPubMedGoogle Scholar
  59. 59.
    Safe S, Abdelrahim M (2005) Sp transcription factor family and its role in cancer. Eur J Cancer 41:2438–2448CrossRefPubMedGoogle Scholar
  60. 60.
    Safe S, Kim K (2004) Nuclear receptor-mediated transactivation through interaction with Sp proteins. Prog Nucleic Acid Res Mol Biol 77:1–36CrossRefPubMedGoogle Scholar
  61. 61.
    Stoner M, Wormke M, Saville B, Samudio I, Qin C, Abdelrahim M, Safe S (2004) Estrogen regulation of vascular endothelial growth factor gene expression in ZR-75 breast cancer cells through interaction of estrogen receptor alpha and SP proteins. Oncogene 23:1052–1063CrossRefPubMedGoogle Scholar
  62. 62.
    Porter W, Saville B, Hoivik D, Safe S (1997) Functional synergy between the transcription factor Sp1 and the estrogen receptor. Mol Endocrinol 11:1569–1580CrossRefPubMedGoogle Scholar
  63. 63.
    Safe S, Kim K (2008) Non-classical genomic estrogen receptor (ER)/specificity protein and ER/activating protein-1 signaling pathways. J Mol Endocrinol 41:263–275CrossRefPubMedGoogle Scholar
  64. 64.
    Hockings JK, Degner SC, Morgan SS, Kemp MQ, Romagnolo DF (2008) Involvement of a specificity proteins-binding element in regulation of basal and estrogen-induced transcription activity of the BRCA1 gene. Breast Cancer Res 10:R29CrossRefPubMedGoogle Scholar
  65. 65.
    Zhu H, Wu H, Liu X, Evans BR, Medina DJ, Liu CG, Yang JM (2008) Role of microRNA miR-27a and miR-451 in the regulation of MDR1/P-glycoprotein expression in human cancer cells. Biochem Pharmacol 76:582–588CrossRefPubMedGoogle Scholar
  66. 66.
    Arisawa T, Tahara T, Shibata T, Nagasaka M, Nakamura M, Kamiya Y, Fujita H, Hasegawa S, Takagi T, Wang FY et al (2007) A polymorphism of microRNA 27a genome region is associated with the development of gastric mucosal atrophy in Japanese male subjects. Dig Dis Sci 52:1691–1697CrossRefPubMedGoogle Scholar
  67. 67.
    Wu H, Zhu S, Mo YY (2009) Suppression of cell growth and invasion by miR-205 in breast cancer. Cell Res 19:439–448CrossRefPubMedGoogle Scholar
  68. 68.
    Shen J, Ambrosone CB, Zhao H (2009) Novel genetic variants in microRNA genes and familial breast cancer. Int J Cancer 124:1178–1182CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC. 2009

Authors and Affiliations

  • Rongxi Yang
    • 1
    • 2
  • Bettina Schlehe
    • 2
  • Kari Hemminki
    • 3
    • 4
  • Christian Sutter
    • 5
  • Peter Bugert
    • 6
  • Barbara Wappenschmidt
    • 7
  • Juliane Volkmann
    • 8
  • Raymonda Varon
    • 9
  • Bernhard H. F. Weber
    • 10
  • Dieter Niederacher
    • 11
  • Norbert Arnold
    • 12
  • Alfons Meindl
    • 8
  • Claus R. Bartram
    • 5
  • Rita K. Schmutzler
    • 7
  • Barbara Burwinkel
    • 1
    • 2
  1. 1.Helmholtz-University Group Molecular EpidemiologyGerman Cancer Research Center (DKFZ)HeidelbergGermany
  2. 2.Division Molecular Biology of Breast Cancer, Department of Gynecology and ObstetricsUniversity of HeidelbergHeidelbergGermany
  3. 3.Division of Molecular Genetic EpidemiologyGerman Cancer Research Center (DKFZ)HeidelbergGermany
  4. 4.Department of Biosciences at NovumKarolinska InstituteHuddingeSweden
  5. 5.Institute of Human GeneticsUniversity of HeidelbergHeidelbergGermany
  6. 6.Institute of Transfusion Medicine and Immunology, Red Cross Blood Service of Baden-Württemberg-HessenUniversity of Heidelberg, Medical Faculty of MannheimMannheimGermany
  7. 7.Division of Molecular Gynaeco-Oncology, Department of Gynaecology and ObstetricsClinical Center University of CologneCologneGermany
  8. 8.Department of Gynaecology and ObstetricsKlinikum rechts der Isar, Technical University of MunichMunichGermany
  9. 9.Institute of Human Genetics, CharitéHumboldt UniversityBerlinGermany
  10. 10.Institute of Human GeneticsUniversity of RegensburgRegensburgGermany
  11. 11.Division of Molecular Genetics, Department of Gynaecology and ObstetricsClinical Center University of DüsseldorfDüsseldorfGermany
  12. 12.Division of Oncology, Department of Gynaecology and ObstetricsUniversity Hospital Schleswig-HolsteinKielGermany

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