Advertisement

Medical Oncology

, 33:135 | Cite as

rs15869 at miRNA binding site in BRCA2 is associated with breast cancer susceptibility

  • Jingjing Cao
  • Chenglin Luo
  • Rui Yan
  • Rui Peng
  • Kaijuan Wang
  • Peng Wang
  • Hua Ye
  • Chunhua Song
Original Paper

Abstract

BRCA1 and BRCA2 mutations confer an increased lifetime risk of breast cancer; however, the associations of microRNA (miRNA) binding site single nucleotide polymorphisms (SNPs) in 3′ untranslated region (3′-UTR) of BRCA1 and BRCA2 with breast cancer (BC) risk were rarely reported. In this case–control study (498 BC patients and 498 matched controls), three SNPs (rs8176318, rs12516 and rs15869) were selected in the 3′-UTR of BRCA1 and BRCA2 genes, which were within miRNA-binding seed regions and might have potential function to regulate the expression of BRCA1/BRCA2. Unconditional logistic regression model was used to analyze the association between three SNPs and BC risk with adjustment of reproductive factors, and Student’s t test was performed to assess relative expression of BRCA2 in human breast cancer cell lines. Multifactor dimensionality reduction method was applied to calculate gene–reproductive factors interactions. A novel finding showed that AC [odds ratio (OR) 1.524; 95% confidence interval (CI) 1.141–2.035] genotype of rs15869 in BRCA2 could increase the risk of BC and recombinant plasmid-pGenesil-1-miR-627 could negatively regulate the expression of BRCA2 in MCF-7 and MDA-MB-231 cells. Gene–reproductive factors interactions analysis revealed that rs15869 together with age at menarche and number of pregnancy could increase the risk of BC by 2.39-fold and TT genotype (OR 0.316; 95% CI 0.130–0.767) of rs8176318 had a significant association with progesterone receptor status in BC patients. Our findings suggest that the miRNA-binding SNPs in BRCA1/BRCA2 and their interaction with reproductive factors might contribute to BC risk, and miR-627 might down-regulate BRCA2 expression in MCF-7 and MDA-MB-231 cells.

Keywords

Breast cancer miRNA binding site Genetic susceptibility Interaction BRCA miRNA-627 

Notes

Acknowledgements

This work was financially supported by the National Natural Science Foundation of China (81202278) and Medical Science and Technology Key Projects of Henan Province (201303005 and 20150374).

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.

Informed consent

Signed informed consent was obtained from each participant. The study was approved by the Ethical Review Committee of Zhengzhou University Committee for Medical and Health Research Ethics.

References

  1. 1.
    Ferlay J, Soerjomataram I, Dikshit R, Eser S, Mathers C, Rebelo M, et al. Cancer incidence and mortality worldwide: sources, methods and major patterns in GLOBOCAN 2012. Int J Cancer. 2015;136(5):E359–86. doi: 10.1002/ijc.29210.CrossRefPubMedGoogle Scholar
  2. 2.
    Torre LA, Bray F, Siegel RL, Ferlay J, Lortet-Tieulent J, Jemal A. Global cancer statistics, 2012. CA Cancer J Clin. 2015;65(2):87–108. doi: 10.3322/caac.21262.CrossRefPubMedGoogle Scholar
  3. 3.
    Chen W, Zheng R, Baade PD, Zhang S, Zeng H, Bray F, et al. Cancer statistics in China, 2015. CA Cancer J Clin. 2016;66(2):115–32. doi: 10.3322/caac.21338.CrossRefPubMedGoogle Scholar
  4. 4.
    Fan L, Strasser-Weippl K, Li J-J, St Louis J, Finkelstein DM, Yu K-D, et al. Breast cancer in China. Lancet Oncol. 2014;15(7):e279–89. doi: 10.1016/s1470-2045(13)70567-9.CrossRefPubMedGoogle Scholar
  5. 5.
    Friebel TM, Domchek SM, Rebbeck TR. Modifiers of cancer risk in BRCA1 and BRCA2 mutation carriers: systematic review and meta-analysis. J Nat Cancer Inst. 2014;106(6):dju091. doi: 10.1093/jnci/dju091.CrossRefPubMedPubMedCentralGoogle Scholar
  6. 6.
    Sapkota Y. Germline DNA variations in breast cancer predisposition and prognosis: a systematic review of the literature. Cytogenet Genome Res. 2014;144(2):77–91. doi: 10.1159/000369045.CrossRefPubMedGoogle Scholar
  7. 7.
    Kurian AW. BRCA1 and BRCA2 mutations across race and ethnicity: distribution and clinical implications. Curr Opin Obstet Gynecol. 2010;22(1):72–8. doi: 10.1097/GCO.0b013e328332dca3.CrossRefPubMedGoogle Scholar
  8. 8.
    Moller P, Hagen AI, Apold J, Maehle L, Clark N, Fiane B, et al. Genetic epidemiology of BRCA mutations–family history detects less than 50% of the mutation carriers. Eur J Cancer. 2007;43(11):1713–7. doi: 10.1016/j.ejca.2007.04.023.CrossRefPubMedGoogle Scholar
  9. 9.
    Couch FJ, Hart SN, Sharma P, Toland AE, Wang X, Miron P, et al. Inherited mutations in 17 breast cancer susceptibility genes among a large triple-negative breast cancer cohort unselected for family history of breast cancer. J Clin Oncol. 2015;33(4):304–11. doi: 10.1200/JCO.2014.57.1414.CrossRefPubMedGoogle Scholar
  10. 10.
    Hoberg-Vetti H, Bjorvatn C, Fiane BE, Aas T, Woie K, Espelid H, et al. BRCA1/2 testing in newly diagnosed breast and ovarian cancer patients without prior genetic counselling: the DNA-BONus study. Eur J Hum Genet EJHG. 2015;. doi: 10.1038/ejhg.2015.196.PubMedGoogle Scholar
  11. 11.
    Schwartz MD, Lerman C, Brogan B, Peshkin BN, Halbert CH, DeMarco T, et al. Impact of BRCA1/BRCA2 counseling and testing on newly diagnosed breast cancer patients. J Clin Oncol. 2004;22(10):1823–9. doi: 10.1200/JCO.2004.04.086.CrossRefPubMedGoogle Scholar
  12. 12.
    Rebbeck TR, Kauff ND, Domchek SM. Meta-analysis of risk reduction estimates associated with risk-reducing salpingo-oophorectomy in BRCA1 or BRCA2 mutation carriers. J Natl Cancer Inst. 2009;101(2):80–7. doi: 10.1093/jnci/djn442.CrossRefPubMedPubMedCentralGoogle Scholar
  13. 13.
    Brewster BL, Rossiello F, French JD, Edwards SL, Wong M, Wronski A, et al. Identification of fifteen novel germline variants in the BRCA1 3′UTR reveals a variant in a breast cancer case that introduces a functional miR-103 target site. Hum Mutat. 2012;33(12):1665–75. doi: 10.1002/humu.22159.CrossRefPubMedGoogle Scholar
  14. 14.
    Chatterjee S, Pal JK. Role of 5′- and 3′-untranslated regions of mRNAs in human diseases. Biol Cell. 2009;101(5):251–62. doi: 10.1042/BC20080104.CrossRefPubMedGoogle Scholar
  15. 15.
    Mishra PJ, Mishra PJ, Banerjee D, Bertino JR. MiRSNPs or MiR-polymorphisms, new players in microRNA mediated regulation of the cell: Introducing microRNA pharmacogenomics. Cell Cycle. 2008;7(7):853–8.CrossRefPubMedGoogle Scholar
  16. 16.
    Kertesz M, Iovino N, Unnerstall U, Gaul U, Segal E. The role of site accessibility in microRNA target recognition. Nat Genet. 2007;39(10):1278–84. doi: 10.1038/ng2135.CrossRefPubMedGoogle Scholar
  17. 17.
    Landi D, Moreno V, Guino E, Vodicka P, Pardini B, Naccarati A, et al. Polymorphisms affecting micro-RNA regulation and associated with the risk of dietary-related cancers: a review from the literature and new evidence for a functional role of rs17281995 (CD86) and rs1051690 (INSR), previously associated with colorectal cancer. Mutat Res. 2011;717(1–2):109–15. doi: 10.1016/j.mrfmmm.2010.10.002.CrossRefPubMedGoogle Scholar
  18. 18.
    Wang S, Tao G, Wu D, Zhu H, Gao Y, Tan Y, et al. A functional polymorphism in MIR196A2 is associated with risk and prognosis of gastric cancer. Mol Carcinog. 2013;52(Suppl 1):E87–95. doi: 10.1002/mc.22017.CrossRefPubMedGoogle Scholar
  19. 19.
    Becher H, Schmidt S, Chang-Claude J. Reproductive factors and familial predisposition for breast cancer by age 50 years. A case–control-family study for assessing main effects and possible gene-environment interaction. Int J Epidemiol. 2003;32(1):38–48. doi: 10.1093/ije/dyg003.CrossRefPubMedGoogle Scholar
  20. 20.
    Andrieu N, Prevost T, Rohan T, Luporsi E, Le MG, Gerber M, et al. Variation in the interaction between familial and reproductive factors on the risk of breast cancer according to age, menopausal status, and degree of familiality. Int J Epidemiol. 2000;29(2):214–23. doi: 10.1093/ije/29.2.214.CrossRefPubMedGoogle Scholar
  21. 21.
    Metcalfe K, Gershman S, Lynch HT, Ghadirian P, Tung N, Kim-Sing C, et al. Predictors of contralateral breast cancer in BRCA1 and BRCA2 mutation carriers. Br J Cancer. 2011;104(9):1384–92. doi: 10.1038/bjc.2011.120.CrossRefPubMedPubMedCentralGoogle Scholar
  22. 22.
    Metcalfe K, Lubinski J, Lynch HT, Ghadirian P, Foulkes WD, Kim-Sing C, et al. Family history of cancer and cancer risks in women with BRCA1 or BRCA2 mutations. J Natl Cancer Inst. 2010;102(24):1874–8. doi: 10.1093/jnci/djq443.CrossRefPubMedGoogle Scholar
  23. 23.
    Scully R, Livingston DM. In search of the tumour-suppressor functions of BRCA1 and BRCA2. Nature. 2000;408(6811):429–32. doi: 10.1038/35044000.CrossRefPubMedPubMedCentralGoogle Scholar
  24. 24.
    Savage KI, Harkin DP. BRCA1, a ‘complex’ protein involved in the maintenance of genomic stability. FEBS J. 2015;282(4):630–46. doi: 10.1111/febs.13150.CrossRefPubMedGoogle Scholar
  25. 25.
    Roy R, Chun J, Powell SN. BRCA1 and BRCA2: different roles in a common pathway of genome protection. Nat Rev Cancer. 2012;12(1):68–78. doi: 10.1038/nrc3181.CrossRefGoogle Scholar
  26. 26.
    Fackenthal JD, Olopade OI. Breast cancer risk associated with BRCA1 and BRCA2 in diverse populations. Nat Rev Cancer. 2007;7(12):937–48. doi: 10.1038/nrc2054.CrossRefPubMedGoogle Scholar
  27. 27.
    Zhou X, Xu X, Wang J, Lin J, Chen W. Identifying miRNA/mRNA negative regulation pairs in colorectal cancer. Sci Rep. 2015;5:12995. doi: 10.1038/srep12995.CrossRefPubMedPubMedCentralGoogle Scholar
  28. 28.
    Salim H, Akbar NS, Zong D, Vaculova AH, Lewensohn R, Moshfegh A, et al. miRNA-214 modulates radiotherapy response of non-small cell lung cancer cells through regulation of p38MAPK, apoptosis and senescence. Br J Cancer. 2012;107(8):1361–73. doi: 10.1038/bjc.2012.382.CrossRefPubMedPubMedCentralGoogle Scholar
  29. 29.
    Subramani A, Alsidawi S, Jagannathan S, Sumita K, Sasaki AT, Aronow B, et al. The brain microenvironment negatively regulates miRNA-768-3p to promote K-ras expression and lung cancer metastasis. Sci Rep. 2013;3:2392. doi: 10.1038/srep02392.CrossRefPubMedPubMedCentralGoogle Scholar
  30. 30.
    Chen X, Xu Y, Cao X, Chen Y, Jiang J, Wang K. Associations of Il-1 family-related polymorphisms with gastric cancer risk and the role of Mir-197 In Il-1f5 expression. Medicine. 2015;94(47):e1982. doi: 10.1097/MD.0000000000001982.CrossRefPubMedPubMedCentralGoogle Scholar
  31. 31.
    Ding L, Jiang Z, Chen Q, Qin R, Fang Y, Li H. A functional variant at miR-520a binding site in PIK3CA alters susceptibility to colorectal cancer in a Chinese Han population. BioMed Res Int. 2015;2015:373252. doi: 10.1155/2015/373252.PubMedPubMedCentralGoogle Scholar
  32. 32.
    Ma J, Guo R, Wang T, Pan X, Lei X. Let-7b binding site polymorphism in the B-cell lymphoma-extra large 3′UTR is associated with fluorouracil resistance of hepatocellular carcinoma. Mol Med Rep. 2015;11(1):677–81. doi: 10.3892/mmr.2014.2692.PubMedGoogle Scholar
  33. 33.
    Pelletier C, Speed WC, Paranjape T, Keane K, Blitzblau R, Hollestelle A, et al. Rare BRCA1 haplotypes including 3′UTR SNPs associated with breast cancer risk. Cell Cycle. 2014;10(1):90–9. doi: 10.4161/cc.10.1.14359.CrossRefGoogle Scholar
  34. 34.
    Dorairaj JJ, Salzman DW, Wall D, Rounds T, Preskill C, Sullivan CA, et al. A germline mutation in the BRCA1 3′UTR predicts Stage IV breast cancer. BMC Cancer. 2014;14:421. doi: 10.1186/1471-2407-14-421.CrossRefPubMedPubMedCentralGoogle Scholar
  35. 35.
    Figueiredo JC, Brooks JD, Conti DV, Poynter JN, Teraoka SN, Malone KE, et al. Risk of contralateral breast cancer associated with common variants in BRCA1 and BRCA2: potential modifying effect of BRCA1/BRCA2 mutation carrier status. Breast Cancer Res Treat. 2011;127(3):819–29. doi: 10.1007/s10549-010-1285-1.CrossRefPubMedGoogle Scholar
  36. 36.
    Erturk E, Cecener G, Polatkan V, Gokgoz S, Egeli U, Tunca B, et al. Evaluation of genetic variations in miRNA-binding sites of BRCA1 and BRCA2 genes as risk factors for the development of early-onset and/or familial breast cancer. Asian Pac J Cancer Prev. 2014;15(19):8319–24. doi: 10.7314/apjcp.2014.15.19.8319.CrossRefPubMedGoogle Scholar
  37. 37.
    Zbuk K, Xie C, Young R, Heydarpour M, Pare G, Davis AD, et al. BRCA2 variants and cardiovascular disease in a multi-ethnic study. BMC Med Genet. 2012;13:56. doi: 10.1186/1471-2350-13-56.CrossRefPubMedPubMedCentralGoogle Scholar
  38. 38.
    Alanazi M, Reddy NP, Shaik JP, Ajaj SA, Jafari AA, Saeed H, et al. Association of BRCA2 variants with cardiovascular disease in Saudi Arabia. Genet Mol Res GMR. 2014;13(2):3876–84. doi: 10.4238/2014.May.16.13.CrossRefPubMedGoogle Scholar
  39. 39.
    Huang L, Wu C, Yu D, Wang C, Che X, Miao X, et al. Identification of common variants in BRCA2 and MAP2K4 for susceptibility to sporadic pancreatic cancer. Carcinogenesis. 2013;34(5):1001–5. doi: 10.1093/carcin/bgt004.CrossRefPubMedGoogle Scholar
  40. 40.
    Liu H, Gao F, Dahlstrom KR, Li G, Sturgis EM, Zevallos JP, et al. A variant at a potentially functional microRNA-binding site in BRIP1 was associated with risk of squamous cell carcinoma of the head and neck. Tumour Biol. 2015;. doi: 10.1007/s13277-015-4682-6.Google Scholar
  41. 41.
    Milne RL, Gaudet MM, Spurdle AB, Fasching PA, Couch FJ, Benitez J, et al. Assessing interactions between the associations of common genetic susceptibility variants, reproductive history and body mass index with breast cancer risk in the breast cancer association consortium: a combined case–control study. Breast Cancer Res BCR. 2010;12(6):R110. doi: 10.1186/bcr2797.CrossRefPubMedGoogle Scholar
  42. 42.
    Campa D, Kaaks R, Le Marchand L, Haiman CA, Travis RC, Berg CD, et al. Interactions between genetic variants and breast cancer risk factors in the breast and prostate cancer cohort consortium. J Natl Cancer Inst. 2011;103(16):1252–63. doi: 10.1093/jnci/djr265.CrossRefPubMedPubMedCentralGoogle Scholar
  43. 43.
    Atchley DP, Albarracin CT, Lopez A, Valero V, Amos CI, Gonzalez-Angulo AM, et al. Clinical and pathologic characteristics of patients with BRCA-positive and BRCA-negative breast cancer. J Clin Oncol. 2008;26(26):4282–8. doi: 10.1200/JCO.2008.16.6231.CrossRefPubMedGoogle Scholar
  44. 44.
    Sanford RA, Song J, Gutierrez-Barrera AM, Profato J, Woodson A, Litton JK, et al. High incidence of germline BRCA mutation in patients with ER low-positive/PR low-positive/HER-2 neu negative tumors. Cancer. 2015;121(19):3422–7. doi: 10.1002/cncr.29572.CrossRefPubMedPubMedCentralGoogle Scholar
  45. 45.
    Dai X, Chen A, Bai Z. Integrative investigation on breast cancer in ER, PR and HER2-defined subgroups using mRNA and miRNA expression profiling. Sci Rep. 2014;4:6566. doi: 10.1038/srep06566.CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2016

Authors and Affiliations

  • Jingjing Cao
    • 1
  • Chenglin Luo
    • 3
  • Rui Yan
    • 1
  • Rui Peng
    • 1
  • Kaijuan Wang
    • 1
    • 2
  • Peng Wang
    • 1
    • 2
  • Hua Ye
    • 1
    • 2
  • Chunhua Song
    • 1
    • 2
  1. 1.Department of Epidemiology and Statistics, College of Public healthZhengzhou UniversityZhengzhouPeople’s Republic of China
  2. 2.Henan Key Laboratory of Tumor EpidemiologyZhengzhouPeople’s Republic of China
  3. 3.Department of Biological SciencesThe University of Texas at El PasoEl PasoUSA

Personalised recommendations