Bioinformatics identification of dysregulated microRNAs in triple negative breast cancer based on microRNA expression profiling

Chen,Junqing; Chen,Zhanhong; Huang,Jian; Chen,Feng; Ye,Weiwu; Ding,Guojun; Wang,Xiaojia

doi:10.3892/ol.2017.7707

Bioinformatics identification of dysregulated microRNAs in triple negative breast cancer based on microRNA expression profiling

Authors:
- Junqing Chen
- Zhanhong Chen
- Jian Huang
- Feng Chen
- Weiwu Ye
- Guojun Ding
- Xiaojia Wang
View Affiliations

Affiliations: Department of Medical Oncology, Zhejiang Cancer Hospital, Hangzhou, Zhejiang 310022, P.R. China, Department of Breast Surgical Oncology, Zhejiang Cancer Hospital, Hangzhou, Zhejiang 310022, P.R. China, Department of Radiology, Zhejiang Cancer Hospital, Hangzhou, Zhejiang 310022, P.R. China
Published online on: December 28, 2017 https://doi.org/10.3892/ol.2017.7707
Pages: 3017-3023
Copyright: © Chen et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

Triple negative breast cancer (TNBC) accounts for approximately 15-20% of all breast cancer cases and is usually more aggressive with a poorer clinical outcome compared with other breast cancer subtypes. Evidence of the involvement of microRNAs (miRNAs) in cancer has provided an opportunity for the development of novel effective therapeutic targets in TNBC. In the present study, the miRNA expression profiles of the human breast cancer cell line, MDA‑MB‑231, and MCF‑7 cells, was evaluated by using miRNA microarray analysis. A total of 107 differentially expressed miRNAs (57 upregulated and 50 downregulated) were identified in MDA‑MB‑231 cells compared with MCF‑7 cells. Five prominently dysregulated miRNAs (miR‑200c‑3p, miR‑221‑3p, miR‑222‑3p, miR‑192‑5p and miR‑146a) were further confirmed by reverse transcription‑quantitative polymerase chain reaction. In addition, gene ontology analysis and pathway enrichment analysis revealed that the dysregulated miRNAs and predicted targets were found to be involved in the mitogen‑activated protein kinase, Wnt, and transforming growth factor‑β signaling pathways, which were known to contribute to TNBC progression and metastasis. Finally, miRNA gene network analyses suggested that miR‑200c may serve as a crucial miRNA in breast cancer. Taken together, these findings may provide a comprehensive view of the function of aberrant miRNAs involved in TNBC, and dysregulated miRNAs hold promise as potential biomarkers and therapeutic targets for patients with TNBC.

View Figures

View References

1	Perou CM, Sørlie T, Eisen MB, van de Rijn M, Jeffrey SS, Rees CA, Pollack JR, Ross DT, Johnsen H, Akslen LA, et al: Molecular portraits of human breast tumours. Nature. 406:747–752. 2000. View Article : Google Scholar : PubMed/NCBI
2	Dent R, Trudeau M, Pritchard KI, Hanna WM, Kahn HK, Sawka CA, Lickley LA, Rawlinson E, Sun P and Narod SA: Triple-negative breast cancer: Clinical features and patterns of recurrence. Clin Cancer Res. 13:4429–4434. 2007. View Article : Google Scholar : PubMed/NCBI
3	Arnedos M, Bihan C, Delaloge S and Andre F: Triple-negative breast cancer: Are we making headway at least. Ther Adv Med Oncol. 4:195–210. 2012. View Article : Google Scholar : PubMed/NCBI
4	Lewis BP, Burge CB and Bartel DP: Conserved seed pairing, often flanked by adenosines, indicates that thousands of human genes are microRNA targets. Cell. 120:15–20. 2005. View Article : Google Scholar : PubMed/NCBI
5	Bartel DP: MicroRNAs: Genomics, biogenesis, mechanism, and function. Cell. 116:281–297. 2004. View Article : Google Scholar : PubMed/NCBI
6	Izumiya M, Tsuchiya N, Okamoto K and Nakagama H: Systematic exploration of cancer-associated microRNA through functional screening assays. Cancer Sci. 102:1615–1621. 2011. View Article : Google Scholar : PubMed/NCBI
7	Gwak JM, Kim HJ, Kim EJ, Chung YR, Yun S, Seo AN, Lee HJ and Park SY: MicroRNA-9 is associated with epithelial-mesenchymal transition, breast cancer stem cell phenotype, and tumor progression in breast cancer. Breast Cancer Res Treat. 147:39–49. 2014. View Article : Google Scholar : PubMed/NCBI
8	Eades G, Wolfson B, Zhang Y, Li Q, Yao Y and Zhou Q.: lincRNA-RoR and miR-145 regulate invasion in triple-negative breast cancer via targeting ARF6. Mol Cancer Res. 13:330–338. 2015. View Article : Google Scholar : PubMed/NCBI
9	Yan LX, Huang XF, Shao Q, Huang MY, Deng L, Wu QL, Zeng YX and Shao JY: MicroRNA miR-21 overexpression in human breast cancer is associated with advanced clinical stage, lymph node metastasis and patient poor prognosis. RNA. 14:2348–2360. 2008. View Article : Google Scholar : PubMed/NCBI
10	Dennis G Jr, Sherman BT, Hosack DA, Yang J, Gao W, Lane HC and Lempicki RA: DAVID: Database for annotation, visualization, and integrated discovery. Genome Biol. 4:P32003. View Article : Google Scholar : PubMed/NCBI
11	Zhang X, Peng Y, Jin Z, Huang W, Cheng Y, Liu Y, Feng X, Yang M, Huang Y, Zhao Z, et al: Integrated miRNA profiling and bioinformatics analyses reveal potential causative miRNAs in gastric adenocarcinoma. Oncotarget. 6:32878–32889. 2015. View Article : Google Scholar : PubMed/NCBI
12	Smoot ME, Ono K, Ruscheinski J, Wang PL and Ideker T: Cytoscape 2.8: New features for data integration and network visualization. Bioinformatics. 27:431–432. 2011. View Article : Google Scholar : PubMed/NCBI
13	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
14	Humphries B, Wang Z, Oom AL, Fisher T, Tan D, Cui Y, Jiang Y and Yang C: MicroRNA-200b targets protein kinase Cα and suppresses triple-negative breast cancer metastasis. Carcinogenesis. 35:2254–2263. 2014. View Article : Google Scholar : PubMed/NCBI
15	Terao M, Fratelli M, Kurosaki M, Zanetti A, Guarnaccia V, Paroni G, Tsykin A, Lupi M, Gianni M, Goodall GJ and Garattini E: Induction of miR-21 by retinoic acid in estrogen receptor-positive breast carcinoma cells: Biological correlates and molecular targets. J Biol Chem. 286:4027–4042. 2011. View Article : Google Scholar : PubMed/NCBI
16	Korpal M, Lee ES, Hu G and Kang Y: The miR-200 family inhibits epithelial-mesenchymal transition and cancer cell migration by direct targeting of E-cadherin transcriptional repressors ZEB1 and ZEB2. J Biol Chem. 283:14910–14914. 2008. View Article : Google Scholar : PubMed/NCBI
17	Gregory PA, Bracken CP, Smith E, Bert AG, Wright JA, Roslan S, Morris M, Wyatt L, Farshid G and Lim YY: An autocrine TGF-beta/ZEB/miR-200 signaling network regulates establishment and maintenance of epithelial-mesenchymal transition. Mol Biol Cell. 22:1686–1698. 2011. View Article : Google Scholar : PubMed/NCBI
18	Knezevic J, Pfefferle AD, Petrovic I, Greene SB, Perou CM and Rosen JM: Expression of miR-200c in claudin-low breast cancer alters stem cell functionality, enhances chemosensitivity and reduces metastatic potential. Oncogene. 34:5997–6006. 2015. View Article : Google Scholar : PubMed/NCBI
19	Ren Y, Han X, Yu K, Sun S, Zhen L, Li Z and Wang S: microRNA-200c downregulates XIAP expression to suppress proliferation and promote apoptosis of triple-negative breast cancer cells. Mol Med Rep. 10:315–321. 2014. View Article : Google Scholar : PubMed/NCBI
20	Castilla MÁ, Díaz-Martín J, Sarrió D, Romero-Pérez L, López-García MÁ, Vieites B, Biscuola M, Ramiro-Fuentes S, Isacke CM and Palacios J: MicroRNA-200 family modulation in distinct breast cancer phenotypes. PLoS One. 7:e477092012. View Article : Google Scholar : PubMed/NCBI
21	Chen J, Tian W, Cai H, He H and Deng Y: Down-regulation of microRNA-200c is associated with drug resistance in human breast cancer. Med Oncol. 29:2527–2534. 2012. View Article : Google Scholar : PubMed/NCBI
22	Howe EN, Cochrane DR, Cittelly DM and Richer JK: miR-200c targets a NF-κB up-regulated TrkB/NTF3 autocrine signaling loop to enhance anoikis sensitivity in triple negative breast cancer. PLoS One. 7:e499872012. View Article : Google Scholar : PubMed/NCBI
23	Howe EN, Cochrane DR and Richer JK: The miR-200 and miR-221/222 microRNA families: Opposing effects on epithelial identity. J Mammary Gland Biol Neoplasia. 17:65–77. 2012. View Article : Google Scholar : PubMed/NCBI
24	Nassirpour R, Mehta PP, Baxi SM and Yin MJ: miR-221 promotes tumorigenesis in human triple negative breast cancer cells. PLoS One. 8:e621702013. View Article : Google Scholar : PubMed/NCBI
25	Søkilde R, Kaczkowski B, Podolska A, Cirera S, Gorodkin J, Møller S and Litman T: Global microRNA analysis of the NCI-60 cancer cell panel. Mol Cancer Ther. 10:375–384. 2011. View Article : Google Scholar : PubMed/NCBI
26	Li Y, Liang C, Ma H, Zhao Q, Lu Y, Xiang Z, Li L, Qin J, Chen Y, Cho WC, et al: miR-221/222 promotes S-phase entry and cellular migration in control of basal-like breast cancer. Molecules. 19:7122–7137. 2014. View Article : Google Scholar : PubMed/NCBI
27	Garcia AI, Buisson M, Bertrand P, Rimokh R, Rouleau E, Lopez BS, Lidereau R, Mikaélian I and Mazoyer S: Down-regulation of BRCA1 expression by miR-146a and miR-146b-5p in triple negative sporadic breast cancers. EMBO Mol Med. 3:279–290. 2011. View Article : Google Scholar : PubMed/NCBI
28	Kumaraswamy E, Wendt KL, Augustine LA, Stecklein SR, Sibala EC, Li D, Gunewardena S and Jensen RA: BRCA1 regulation of epidermal growth factor receptor (EGFR) expression in human breast cancer cells involves microRNA-146a and is critical for its tumor suppressor function. Oncogene. 34:4333–4346. 2015. View Article : Google Scholar : PubMed/NCBI
29	Giltnane JM and Balko JM: Rationale for targeting the Ras/MAPK pathway in triple-negative breast cancer. Discov Med. 17:275–283. 2014.PubMed/NCBI
30	Hashimoto K, Tsuda H, Koizumi F, Shimizu C, Yonemori K, Ando M, Kodaira M, Yunokawa M, Fujiwara Y and Tamura K: Activated PI3K/AKT and MAPK pathways are potential good prognostic markers in node-positive, triple-negative breast cancer. Ann Oncol. 25:1973–1979. 2014. View Article : Google Scholar : PubMed/NCBI
31	Lehmann BD, Bauer JA, Chen X, Sanders ME, Chakravarthy AB, Shyr Y and Pietenpol JA: Identification of human triple-negative breast cancer subtypes and preclinical models for selection of targeted therapies. J Clin Invest. 121:2750–2767. 2011. View Article : Google Scholar : PubMed/NCBI
32	Bilir B, Kucuk O and Moreno CS: Wnt signaling blockage inhibits cell proliferation and migration, and induces apoptosis in triple-negative breast cancer cells. J Transl Med. 11:2802013. View Article : Google Scholar : PubMed/NCBI
33	Wahdan-Alaswad R, Harrell JC, Fan Z, Edgerton SM, Liu B and Thor AD: Metformin attenuates transforming growth factor beta (TGF-β) mediated oncogenesis in mesenchymal stem-like/claudin-low triple negative breast cancer. Cell Cycle. 15:1046–1059. 2016. View Article : Google Scholar : PubMed/NCBI