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Öz

In recent years studies are accelerated in determining the possible molecular mechanisms of breast cancer in addition to the development of many treatment strategies. However these treatment strategies cause different curative responses and/or development of adjuvant therapy resistance in breast cancer patients. On the other hand, with more recent studies declaring the roles of miRNAs as the regulators of gene expression miRNAs became new potential therapeutic targets and thus evaluated as candidate diagnostic and prognostic indicators of breast cancer. Eventually it was expected that in near future miRNAs have parts in both tumor classification and efficient treatment strategies as novel biomarkers and prognostic indicators as well as in the classification of breast cancer according to tumor gene expression markers. İn addition it was thought that creating of miRNA expression models could explain the molecular basis of the subtypes and also could contribute to the development of targeted treatment models. Thus the biological roles of miRNAs in several diseases and effective mechanisms in breast cancers will be discussed in this review.

Anahtar Kelimeler

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miRNAlar ve Meme Kanserindeki Etkileri

Öz

Meme kanserinde etkili olan moleküler mekanizmalarının tarifi için son yıllarda yoğun çalışmalar yapılmaktadır. Bununla birlikte bugüne kadar, bu hastalık için birçok tedavi stratejisi geliştirilmiştir. Ancak ne yazık ki bu tedaviler, hastalarda farklı yanıtların ve/veya adjuvan tedavi resistansı gelişiminin oluşumuna neden olmuştur. miRNAların gen ekspresyonunun regülatörleri olarak görev yaptıklarının belirlenmesinden sonra hem potansiyel terapötik hedef haline gelmiş hem de aday diagnostik ve prognostik indikatör olarak değerlendirilmiştir. Sonuçta meme kanseri gen ekspresyon işaretlerine dayanan alt tiplendirmesine benzer olarak miRNA işaretlerinin de tümörlerin sınıflandırılmasında biyomarker ve prognostik indikatör olarak kullanılmasının yakın gelekte mümkün olacağı ve bu şekilde bireysel rasyonel tedavilerin sağlanabileceği gösterilmiştir. Ayrıca miRNA ekspresyon modellemelerinin yapılması, bu alt tiplerin altında yatan moleküler temelleri de açıklayabilir ve hedeflenen tedavi modellerinin geliştirilmesine katkıda bulunabileceği düşünülmektedir.  Bu derlemede miRNAların genel etki mekanizmaları ve meme kanserindeki etki mekanizmaları tartışılacaktır.

Anahtar Kelimeler

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Kaynakça

1. Nakahara K, Carthew RW. Expanding roles for miRNAs and siRNAs in cell regulation. Curr Opin Cell Biol. 2004;16(2):127-133.
2. Yu Z, Baserga R, Chen L, Wang C, Lisanti MP, Pestell RG. microRNA, cell cycle, and human breast cancer. Am J Pathol. 2010;176(3):1058-64.
3. Reinhart BJ, Bartel DP: Small RNAs correspond to centromere heterochromatic repeats. Science 2002, 297:1831
4. Lee RC, Feinbaum RL, Ambros V. 1993. The C. elegans heterochronic gene lin-4 encodes small RNAs with antisense complementarity to lin-14. Cell 75:843–54
5. Wightman B, Ha I, Ruvkun G. 1993. Posttranscriptional regulation of the heterochronic gene lin-14 by lin-4 mediates temporal pattern formation in C. elegans. Cell 75:855–62
6. Bartel DP.MicroRNAs: genomics, biogenesis, mechanism, and function. Cell. 2004;23;116(2):281-97.
7. Michael T. McManus. Small RNAs and Immunity 2004, Immunity, Vol. 21, 747–756.
8. O’Donnell KA, Wentzel EA, Zeller KI, Dang CV, Mendell JT: c-Myc-regulated microRNAs modulate E2F1 expression. Nature 2005, 435:839-843

9. Alvarez-Garcia I, Miska EA. MicroRNA functions in animal development and human disease. Development. 2005 Nov;132(21):4653-62.
10. Aagaard L, Rossi JJ. RNAi therapeutics: principles, prospects and challenges. Adv Drug Deliv Rev. 2007;59(2-3):75-86.
11. Carthew RW. Gene regulation by microRNAs. Curr Opin Genet Dev. 2006;16(2):203-8.
12. Cai X, Hagedorn CH, Cullen BR. 2004. Human microRNAs are processed from capped,polyadenylated transcripts that can also function as mRNAs. RNA 10:1957–66.
13. Lee Y, Kim M, Han J, Yeom KH, Lee S, et al. 2004. MicroRNA genes are transcribed by RNA polymerase II. EMBO J. 23:4051–60
14. Borchert GM, Lanier W, Davidson BL. 2006. RNA polymerase III transcribes human microRNAs. Nat. Struct. Mol. Biol. 13:1097–101
15. Bushati N, Cohen SM. microRNA functions. Annu Rev Cell Dev Biol. 2007 23:175-205.
16. Friedman RC, Farh KK, Burge CB, Bartel DP. Most mammalian mRNAs are conserved targets of microRNAs. Genome Res. 2009;19(1):92-105.
17. Ruby JG, Jan C, Player C, Axtell MJ, Lee W, et al. 2006. Large-scale sequencing reveals 21URNAs and additional microRNAs and endogenous siRNAs in C. elegans. Cell 127:1193–207 Scherr M, Eder M.Gene silencing by small regulatory RNAs in mammalian cells. Cell Cycle. 2007;15;6(4):444-9.
18. Carè A, Catalucci D, Felicetti F, Bonci D, Addario A, Gallo P, Bang ML, Segnalini P, Gu Y, Dalton ND, Elia L, Latronico MV, Hİydal M, Autore C, Russo MA, Dorn GW 2nd, Ellingsen O, Ruiz-Lozano P, Peterson KL, Croce CM, Peschle C, Condorelli G. MicroRNA133 controls cardiac hypertrophy. Nat Med. 2007;13(5):613-8.
19. Xiao, C., & Rajewsky, K. MicroRNA control in the immune system: basic principles. Cell 2009;136(1), 26–36.
20. Cameron JE, Yin Q, Fewell C, Lacey M, McBride J, Wang X, Lin Z, Schaefer BC, Flemington EK. EpsteinBarr virus latent membrane protein 1 induces cellular MicroRNA miR-146a, a modulator of lymphocyte signaling pathways. Journal of Virology 2008;82(4), 1946–1958.
21. Gonzalez-Alegre P. Therapeutic RNA interference for neurodegenerative diseases: from promise to progress. Pharmacol Ther 2007 114: 34–55
22. McCaffrey AP, Meuse L, Pham TT, Conklin DS, Hannon GJ, Kay MA. RNA interference in adult mice. Nature 2002;418:38–39.
23. Hammond SM. RNAi, microRNAs, and human disease. Cancer Chemother Pharmacol. 2006 Nov;58 Suppl 1:s63-8.
24. Calin GA, Sevignani C, Dumitru CD, Hyslop T, Noch E, Yendamuri S, Shimizu M, Rattan S, Bullrich F, Negrini M, Croce CM. Human microRNA genes are frequently located at fragile sites and genomic regions involved in cancers. Proc Natl Acad Sci U S A. 2004;2;101(9):2999-3004
25. Lu J, Getz G, Miska EA, Alvarez-Saavedra E, Lamb J, Peck D, Sweet-Cordero A, Ebert BL, Mak RH, Ferrando AA, Downing JR, Jacks T, Horvitz HR, Golub TR. MicroRNA expression profiles classify human cancers. Nature. 2005;9;435(7043):834-8.
26. Guarnieri DJ, DiLeone RJ. MicroRNAs: A new class of generegulators. Ann.Med. 2008;40(3):197-208
27. Johnson SM, Grosshans H, Shingara J, Byrom M, Jarvis R, Cheng A, Labourier E, Reinert KL, Brown D, Slack FJ. RAS is regulated by the let-7 microRNA family. Cell. 2005;11;120(5):635-47
28. Sevignani C, Calin GA, Siracusa LD, Croce CM. Mammalian microRNAs: a small world for fine-tuning gene expression. Mamm Genome. 2006;17(3):189-202.
29. Heneghan HM, Miller N, Lowery AJ, Sweeney KJ, Kerin MJ. MicroRNAs as Novel Biomarkers for Breast Cancer J Oncol. 2009;2009:950201.
30. Liu CG, Calin GA, Meloon B, Gamliel N, Sevignani C, Ferracin M, Dumitru CD, Shimizu M, Zupo S, Dono M, Alder H, Bullrich F, Negrini M, Croce CM. An oligonucleotide microchip for genomewide microRNA profiling in human and mouse tissues. Proc Natl Acad Sci USA. 2004;101(26):9740-4.
31. Shenouda SK, Alahari SK. MicroRNA function in cancer: oncogene or a tumor suppressor? Cancer Metastasis Rev. 2009;28:369-378.
32. Jiang J, Lee EJ, Gusev Y, Schmittgen TD. Realtime expression profiling of microRNA precursors in human cancer cell lines. Nucleic Acids Res. 2005 Sep 28;33(17):5394-403.
33. Shen J, Ambrosone CB, Zhao H. Novel genetic variants in microRNA genes and familial breast cancer. Int J Cancer 2009;124(5):1178–82.
34. O'Day E, Lal A. MicroRNAs and their target gene networks in breast cancer. Breast Cancer Res. 2010;12(2):201.
35. Liu Q, Fu H, Sun F, Zhang H, Tie Y, Zhu J, Xing R, Sun Z, Zheng X. miR-16 family induces cell cycle arrest by regulating multiple cell cycle genes. Nucleic Acids Res 2008;36:5391–5404.
36. Calin GA, Cimmino A, Fabbri M, Ferracin M, Wojcik SE, Shimizu M, Taccioli C, Zanesi N, Garzon R, Aqeilan RI, Alder H, Volinia S, Rassenti L, Liu X, Liu CG, Kipps TJ, Negrini M, Croce CM. MiR-15a and miR-16-1 cluster functions in human leukemia, Proc Natl Acad Sci USA 2008;105:5166–5171.
37. Hossain A, Kuo MT, Saunders GF. Mir-17-5p regulates breast cancer cell proliferation by inhibiting translation of AIB1 mRNA. Mol Cell Biol 2006;26:8191–8201.
38. Yu Z, Wang C, Wang M, Li Z, Casimiro MC, Liu M, Wu K, Whittle J, Ju X, Hyslop T, McCue P, Pestell RG. A cyclin D1/microRNA 17/20 regulatory feedback loop in control of breast cancer cell proliferation. J Cell Biol 2008;182:509–517.
39. Miller TE, Ghoshal K, Ramaswamy B, Roy S, Datta J, Shapiro CL, Jacob S, Majumder S. MicroRNA-221/222 confers tamoxifen resistance in breast cancer by targeting p27Kip J Biol Chem 2008;283:29897–29903.
40. Zhao JJ, Lin J, Yang H, Kong W, He L, Ma X, Coppola D, Cheng JQ. MicroRNA-221/222 negatively regulates estrogen receptor alpha and is associated with tamoxifen resistance in breast cancer. J Biol Chem 2008;283:31079– 3108
41. Sun F, Fu H, Liu Q, Tie Y, Zhu J, Xing R, Sun Z, Zheng X. Downregulation of CCND1 and CDK6 by miR-34a induces cell cycle arrest. FEBS Lett 2008;582:1564–1568.
42. Eiriksdottir G, Johannesdottir G, Ingvarsson S, Bjornsdottir IB, Jonasson JG, Agnarsson BA, Hallgrimsson J, Gudmundsson J, Egilsson V, Sigurdsson H, Barkardottir RB. Mapping loss of heterozygosity at chromosome 13q: loss at 13q12–q13 is associated with breast tumour progression and poor prognosis. Eur J Cancer 1998;34:2076–2081.
43. Kondo N, Toyama T, Sugiura H, Fujii Y, Yamashita H. miR-206 Expression is down-regulated in estrogen receptor alpha-positive human breast cancer. Cancer Res 2008;68:5004–5008.
44. Korpal M, Lee ES, Hu G, Kang Y. The miR-200 family inhibits epithelialmesenchymal transition and cancer cell migration by direct targeting of E-cadherin transcriptional repressors ZEB1 and ZEB2. J Biol Chem 2008; 283:14910149
45. Iliopoulos D, Polytarchou C, Hatziapostolou M, Kottakis F, Maroulakou IG, Struhl K, Tsichlis PN: MicroRNAs diff erentially regulated by Akt isoforms control EMT and stem cell renewal in cancer cells. Sci Signal 2009, 2:ra62.
46. Clarke MF, Fuller M. Stem cells and cancer: two faces of eve. Cell 2006;124:1111-1115.
47. Yu F, Yao H, Zhu P, Zhang X, Pan Q, Gong C, Huang Y, Hu X, Su F, Lieberman J, Song E. let-7 regulates self renewal and tumorigenicity of breast cancer cells. Cell 2007;131:1109-1123.
48. Dangi-Garimella S, Yun J, Eves EM, Newman M, Erkeland SJ, Hammond SM, Minn AJ, Rosner MR. Raf kinase inhibitory protein suppresses a metastasis signalling cascade involving LIN28 and let-7. EMBO J 2009;28:34735
49. Valastyan S, Reinhardt F, Benaich N, Calogrias D, Szasz AM, Wang ZC, Brock JE, Richardson AL, Weinberg RA. A pleiotropically acting microRNA, miR-31, inhibits breast cancer metastasis. Cell 2009;137:1032-1046. 5 Volinia S, Calin GA, Liu CG, Ambs S, Cimmino A, Petrocca F, Visone R, Iorio M,Roldo C, Ferracin M, Prueitt
50. RL, Yanaihara N, Lanza G, Scarpa A, Vecchione A, Negrini M, Harris CC, Croce CM. A microRNA expression signature of human solid tumors defi nes cancer gene targets. Proc Natl Acad Sci USA 2006;103:2257-2261. 5 Kong W, Yang H, He L, Zhao J-j, Coppola D, Dalton
51. WS, Cheng JQ. MicroRNA-155 is regulated by the transforming growth factor beta/Smad pathway and contributes to epithelial cell plasticity by targeting RhoA. Mol Cell Biol 2008;28:6773-6784. 5 Ma L, Teruya-Feldstein J, Weinberg RA. Tumour invasion and metastasis initiated by microRNA-10b in breast cancer. Nature, 2007;449(7163), 682–688. 5 Gee HE, Camps
52. C, Buffa FM, Colella S, Sheldon H, Gleadle JM, Ragoussis J,Harris AL. MicroRNA-10b and breast cancer metastasis. Nature 2008;455:E8–E9. 5 Tavazoie SF, Alarcon C, Oskarsson T, Padua D, Wang
53. Q, Bos PD, Gerald WL, Massague J. Endogenous human microRNAs that suppress breast cancer metastasis. Nature 2008; 451(7175), 147–152.