Identification of dysregulated microRNAs associated with diagnosis and prognosis in triple‑negative breast cancer: An in silico study

  • Authors:
    • Chunni Fan
    • Ning Liu
  • View Affiliations

  • Published online on: April 2, 2019     https://doi.org/10.3892/or.2019.7094
  • Pages: 3313-3324
Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )
Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )


Abstract

Triple‑negative breast cancer (TNBC) is a highly aggressive subtype of breast cancer with limited treatment options combined with poor rates of survival. Given the lack of appropriate prognostic biomarkers for TNBC patients, the present study aimed to identify potential dysregulated miRNAs capable of providing a diagnosis and predicting overall survival for TNBC patients. A total of 289 miRNAs were aberrantly regulated in TNBC tissue compared to adjacent, non‑cancerous tissues and 96 microRNAs (miRNAs) in TNBC compared with non‑triple‑negative breast cancer (nTNBC) samples. Receiver operating characteristic (ROC) curve analysis suggested that 4 miRNAs (hsa‑miR‑10a, hsa‑miR‑18a, hsa‑miR‑135b and hsa‑miR‑577) had diagnostic value [area under curve (AUC) >0.8]. A 4‑miRNA signature consisting of hsa‑miR‑148b, hsa‑miR‑203a, hsa‑miR‑203b and hsa‑miR‑3922 was constructed for prediction of prognosis. A multivariate Cox's proportional hazards regression model indicated that the 4‑miRNA signature was an independent prognostic factor of other clinical variables in patients with TNBC. Functional analysis of the target genes of the miRNA signature demonstrated that the prolactin signaling pathway and miRNAs in cancer were significantly enriched. In conclusion, the results in the present study may highlight efficient biomarkers for the diagnosis of TNBC and its prognosis. In‑depth exploitation of these miRNAs will help define and develop novel molecular therapeutic strategies and improve prognosis for TNBC patients.

References

1 

Torre LA, Bray F, Siegel RL, Ferlay J, Lortet-Tieulent J and Jemal A: Global cancer statistics, 2012. CA Cancer J Clin. 65:87–108. 2015. View Article : Google Scholar : PubMed/NCBI

2 

Chen W, Zheng R, Baade PD, Zhang S, Zeng H, Bray F, Jemal A, Yu XQ and He J: Cancer statistics in China, 2015. CA Cancer J Clin. 66:115–132. 2016. View Article : Google Scholar : PubMed/NCBI

3 

Carey LA, Perou CM, Livasy CA, Dressler LG, Cowan D, Conway K, Karaca G, Troester MA, Tse CK, Edmiston S, et al: Race, breast cancer subtypes, and survival in the Carolina Breast Cancer Study. JAMA. 295:2492–2502. 2006. View Article : Google Scholar : PubMed/NCBI

4 

Sorlie T, Tibshirani R, Parker J, Hastie T, Marron JS, Nobel A, Deng S, Johnsen H, Pesich R, Geisler S, et al: Repeated observation of breast tumor subtypes in independent gene expression data sets. Proc Natl Acad Sci USA. 100:8418–8423. 2003. View Article : Google Scholar : PubMed/NCBI

5 

Croce CM and Calin GA: miRNAs, cancer, and stem cell division. Cell. 122:6–7. 2005. View Article : Google Scholar : PubMed/NCBI

6 

Cascione L, Gasparini P, Lovat F, Carasi S, Pulvirenti A, Ferro A, Alder H, He G, Vecchione A, Croce CM, et al: Integrated microRNA and mRNA signatures associated with survival in triple negative breast cancer. PLoS One. 8:e559102013. View Article : Google Scholar : PubMed/NCBI

7 

Gasparini P, Cascione L, Fassan M, Lovat F, Guler G, Balci S, Irkkan C, Morrison C, Croce CM, Shapiro CL, et al: microRNA expression profiling identifies a four microRNA signature as a novel diagnostic and prognostic biomarker in triple negative breast cancers. Oncotarget. 5:1174–1184. 2014. View Article : Google Scholar : PubMed/NCBI

8 

Kleivi Sahlberg K, Bottai G, Naume B, Burwinkel B, Calin GA, Børresen-Dale AL and Santarpia L: A serum microRNA signature predicts tumor relapse and survival in triple-negative breast cancer patients. Clin Cancer Res. 21:1207–1214. 2015. View Article : Google Scholar : PubMed/NCBI

9 

Robinson MD, McCarthy DJ and Smyth GK: edgeR: A BioconductoR package for differential expression analysis of digital gene expression data. Bioinformatics. 26:139–140. 2010. View Article : Google Scholar : PubMed/NCBI

10 

Yu G, Wang LG, Han Y and He QY: clusterProfiler: An R package for comparing biological themes among gene clusters. OMICS. 16:284–287. 2012. View Article : Google Scholar : PubMed/NCBI

11 

Dawson SJ, Provenzano E and Caldas C: Triple negative breast cancers: Clinical and prognostic implications. Eur J Cancer. 45 (Suppl 1):S27–S40. 2009. View Article : Google Scholar

12 

Santarpia L, Qi Y, Stemke-Hale K, Wang B, Young EJ, Booser DJ, Holmes FA, O'Shaughnessy J, Hellerstedt B, Pippen J, et al: Mutation profiling identifies numerous rare drug targets and distinct mutation patterns in different clinical subtypes of breast cancers. Breast Cancer Res Treat. 134:333–343. 2012. View Article : Google Scholar : PubMed/NCBI

13 

Zhang L, Huang J, Yang N, Greshock J, Megraw MS, Giannakakis A, Liang S, Naylor TL, Barchetti A, Ward MR, et al: microRNAs exhibit high frequency genomic alterations in human cancer. Proc Natl Acad Sci USA. 103:9136–9141. 2006. View Article : Google Scholar : PubMed/NCBI

14 

Tan Y, Zhang B, Wu T, Skogerbø G, Zhu X, Guo X, He S and Chen R: Transcriptional inhibiton of Hoxd4 expression by miRNA-10a in human breast cancer cells. BMC Mol Biol. 10:122009. View Article : Google Scholar : PubMed/NCBI

15 

Yan Y, Wang Q, Yan XL, Zhang Y, Li W, Tang F, Li X and Yang P: miR-10a controls glioma migration and invasion through regulating epithelial-mesenchymal transition via EphA8. FEBS Lett. 589:756–765. 2015. View Article : Google Scholar : PubMed/NCBI

16 

Markou A, Sourvinou I, Vorkas PA, Yousef GM and Lianidou E: Clinical evaluation of microRNA expression profiling in non small cell lung cancer. Lung Cancer. 81:388–396. 2013. View Article : Google Scholar : PubMed/NCBI

17 

Gaur A, Jewell DA, Liang Y, Ridzon D, Moore JH, Chen C, Ambros VR and Israel MA: Characterization of microRNA expression levels and their biological correlates in human cancer cell lines. Cancer Res. 67:2456–2468. 2007. View Article : Google Scholar : PubMed/NCBI

18 

Ma L: Role of miR-10b in breast cancer metastasis. Breast Cancer Res. 12:2102010. View Article : Google Scholar : PubMed/NCBI

19 

Han J, Kim D and Morris KV: Promoter-associated RNA is required for RNA-directed transcriptional gene silencing in human cells. Proc Natl Acad Sci USA. 104:12422–12427. 2007. View Article : Google Scholar : PubMed/NCBI

20 

Liu WH, Yeh SH, Lu CC, Yu SL, Chen HY, Lin CY, Chen DS and Chen PJ: MicroRNA-18a prevents estrogen receptor-alpha expression, promoting proliferation of hepatocellular carcinoma cells. Gastroenterology. 136:683–693. 2009. View Article : Google Scholar : PubMed/NCBI

21 

Calvano Filho CM, Calvano-Mendes DC, Carvalho KC, Maciel GA, Ricci MD, Torres AP, Filassi JR and Baracat EC: Triple-negative and luminal A breast tumors: Differential expression of miR-18a-5p, miR-17-5p, and miR-20a-5p. Tumour Biol. 35:7733–7741. 2014. View Article : Google Scholar : PubMed/NCBI

22 

Fan YX, Dai YZ, Wang XL, Ren YQ, Han JJ and Zhang H: MiR-18a upregulation enhances autophagy in triple negative cancer cells via inhibiting mTOR signaling pathway. Eur Rev Med Pharmacol Sci. 20:2194–2200. 2016.PubMed/NCBI

23 

Sha LY, Zhang Y, Wang W, Sui X, Liu SK, Wang T and Zhang H: MiR-18a upregulation decreases dicer expression and confers paclitaxel resistance in triple negative breast cancer. Eur Rev Med Pharmacol Sci. 20:2201–2208. 2016.PubMed/NCBI

24 

Dai X, Chen A and Bai Z: Integrative investigation on breast cancer in ER, PR and HER2-defined subgroups using mRNA and miRNA expression profiling. Sci Rep. 4:65662014. View Article : Google Scholar : PubMed/NCBI

25 

Uva P, Cossu-Rocca P, Loi F, Pira G, Murgia L, Orrù S, Floris M, Muroni MR, Sanges F, Carru C, et al: miRNA-135b contributes to triple negative breast cancer molecular heterogeneity: Different expression profile in basal-like versus non-basal-like phenotypes. Int J Med Sci. 15:536–548. 2018. View Article : Google Scholar : PubMed/NCBI

26 

Paszek S, Gablo N, Barnas E, Szybka M, Morawiec J, Kołacińska A and Zawlik I: Dysregulation of microRNAs in triple-negative breast cancer. Ginekol Pol. 88:530–536. 2017. View Article : Google Scholar : PubMed/NCBI

27 

Buffa FM, Camps C, Winchester L, Snell CE, Gee HE, Sheldon H, Taylor M, Harris AL and Ragoussis J: microRNA-associated progression pathways and potential therapeutic targets identified by integrated mRNA and microRNA expression profiling in breast cancer. Cancer Res. 71:5635–5645. 2011. View Article : Google Scholar : PubMed/NCBI

28 

Pan HW, Li SC and Tsai KW: MicroRNA dysregulation in gastric cancer. Curr Pharm Des. 19:1273–1284. 2013. View Article : Google Scholar : PubMed/NCBI

29 

Tatarano S, Chiyomaru T, Kawakami K, Enokida H, Yoshino H, Hidaka H, Yamasaki T, Kawahara K, Nishiyama K, Seki N, et al: miR-218 on the genomic loss region of chromosome 4p15.31 functions as a tumor suppressor in bladder cancer. Int J Oncol. 39:13–21. 2011.PubMed/NCBI

30 

Kolacinska A, Morawiec J, Fendler W, Malachowska B, Morawiec Z, Szemraj J, Pawlowska Z, Chowdhury D, Choi YE, Kubiak R, et al: Association of microRNAs and pathologic response to preoperative chemotherapy in triple negative breast cancer: Preliminary report. Mol Biol Rep. 41:2851–2857. 2014. View Article : Google Scholar : PubMed/NCBI

31 

Yin C, Mou Q, Pan X, Zhang G, Li H and Sun Y: MiR-577 suppresses epithelial-mesenchymal transition and metastasis of breast cancer by targeting Rab25. Thorac Cancer. 9:472–479. 2018. View Article : Google Scholar : PubMed/NCBI

32 

Zhao G, Zhang JG, Liu Y, Qin Q, Wang B, Tian K, Liu L, Li X, Niu Y, Deng SC, et al: miR-148b functions as a tumor suppressor in pancreatic cancer by targeting AMPKalpha1. Mol Cancer Ther. 12:83–93. 2013. View Article : Google Scholar : PubMed/NCBI

33 

Yang JS, Li BJ, Lu HW, Chen Y, Lu C, Zhu RX, Liu SH, Yi QT, Li J and Song CH: Serum miR-152, miR-148a, miR-148b, and miR-21 as novel biomarkers in non-small cell lung cancer screening. Tumour Biol. 36:3035–3042. 2015. View Article : Google Scholar : PubMed/NCBI

34 

Zhang JG, Shi Y, Hong DF, Song M, Huang D, Wang CY and Zhao G: MiR-148b suppresses cell proliferation and invasion in hepatocellular carcinoma by targeting WNT1/β-catenin pathway. Sci Rep. 5:80872015. View Article : Google Scholar : PubMed/NCBI

35 

Ziari K, Zarea M, Gity M, Fayyaz AF, Yahaghi E, Darian EK and Hashemian AM: Downregulation of miR-148b as biomarker for early detection of hepatocellular carcinoma and may serve as a prognostic marker. Tumour Biol. 37:5765–5768. 2016. View Article : Google Scholar : PubMed/NCBI

36 

Furuta M, Kozaki KI, Tanaka S, Arii S, Imoto I and Inazawa J: miR-124 and miR-203 are epigenetically silenced tumor-suppressive microRNAs in hepatocellular carcinoma. Carcinogenesis. 31:766–776. 2010. View Article : Google Scholar : PubMed/NCBI

37 

Saini S, Majid S, Yamamura S, Tabatabai L, Suh SO, Shahryari V, Chen Y, Deng G, Tanaka Y and Dahiya R: Regulatory role of mir-203 in prostate cancer progression and metastasis. Clin Cancer Res. 17:5287–5298. 2011. View Article : Google Scholar : PubMed/NCBI

38 

Zhang Z, Zhang B, Li W, Fu L, Fu L, Zhu Z and Dong JT: Epigenetic silencing of miR-203 upregulates SNAI2 and contributes to the invasiveness of malignant breast cancer cells. Genes Cancer. 2:782–791. 2011. View Article : Google Scholar : PubMed/NCBI

39 

Chiang Y, Song Y, Wang Z, Chen Y, Yue Z, Xu H, Xing C and Liu Z: Aberrant expression of miR-203 and its clinical significance in gastric and colorectal cancers. J Gastrointest Surg. 15:63–70. 2011. View Article : Google Scholar : PubMed/NCBI

40 

Greither T, Grochola LF, Udelnow A, Lautenschlager C, Wurl P and Taubert H: Elevated expression of microRNAs 155, 203, 210 and 222 in pancreatic tumors is associated with poorer survival. Int J Cancer. 126:73–80. 2010. View Article : Google Scholar : PubMed/NCBI

41 

Hezova R, Kovarikova A, Srovnal J, Zemanova M, Harustiak T, Ehrmann J, Hajduch M, Svoboda M, Sachlova M and Slaby O: Diagnostic and prognostic potential of miR-21, miR-29c, miR-148 and miR-203 in adenocarcinoma and squamous cell carcinoma of esophagus. Diagn Pathol. 10:422015. View Article : Google Scholar : PubMed/NCBI

42 

Frisch SM and Francis H: Disruption of epithelial cell-matrix interactions induces apoptosis. J Cell Biol. 124:619–626. 1994. View Article : Google Scholar : PubMed/NCBI

43 

Streuli CH and Gilmore AP: Adhesion-mediated signaling in the regulation of mammary epithelial cell survival. J Mammary Gland Biol Neoplasia. 4:183–191. 1999. View Article : Google Scholar : PubMed/NCBI

44 

Park SH, Riley P IV and Frisch SM: Regulation of anoikis by deleted in breast cancer-1 (DBC1) through NF-κB. Apoptosis. 18:949–962. 2013. View Article : Google Scholar : PubMed/NCBI

45 

Garofalo M, Leva GD and Croce CM: MicroRNAs as anti-cancer therapy. Curr Pharm Des. 20:5328–5335. 2014. View Article : Google Scholar : PubMed/NCBI

46 

Yarden Y and Sliwkowski MX: Untangling the ErbB signalling network. Nat Rev Mol Cell Biol. 2:127–137. 2001. View Article : Google Scholar : PubMed/NCBI

47 

DiGiovanna MP, Stern DF, Edgerton SM, Whalen SG, Moore D II and Thor AD: Relationship of epidermal growth factor receptor expression to ErbB-2 signaling activity and prognosis in breast cancer patients. J Clin Oncol. 23:1152–1160. 2005. View Article : Google Scholar : PubMed/NCBI

48 

Vonderhaar BK: Prolactin involvement in breast cancer. Endocr Relat Cancer. 6:389–404. 1999. View Article : Google Scholar : PubMed/NCBI

Related Articles

Journal Cover

June 2019
Volume 41 Issue 6

Print ISSN: 1021-335X
Online ISSN:1791-2431

Sign up for eToc alerts

Recommend to Library

Copy and paste a formatted citation
APA
Fan, C., & Fan, C. (2019). Identification of dysregulated microRNAs associated with diagnosis and prognosis in triple‑negative breast cancer: An in silico study. Oncology Reports, 41, 3313-3324. https://doi.org/10.3892/or.2019.7094
MLA
Fan, C., Liu, N."Identification of dysregulated microRNAs associated with diagnosis and prognosis in triple‑negative breast cancer: An in silico study". Oncology Reports 41.6 (2019): 3313-3324.
Chicago
Fan, C., Liu, N."Identification of dysregulated microRNAs associated with diagnosis and prognosis in triple‑negative breast cancer: An in silico study". Oncology Reports 41, no. 6 (2019): 3313-3324. https://doi.org/10.3892/or.2019.7094