Screening Key Genes and Pathways in Triple-negative Breast Cancer by Bioinformatics Analysis

Abstract

Abstract: Objective To screen key genes and pathways associated with tumorigenesis and progression of triple-negative breast cancer (TNBC) by using bioinformatics analysis. Methods Two gene expression profilings containing TNBC (GSE76124) and normal mammary (GSE112825) tissue samples were obtained from Gene Expression Omnibus (GEO). R software was used to identify differentially expressed genes. Gene Ontology (GO) function analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis were further performed by DAVID. STRING and Cytoscape were used to construct protein-protein interaction(PPI) network. Furthermore, hub genes, core modules and seed genes were screened out. Results A total of 1,091 differentially expressed genes were screened out. The results of GO function analysis and KEGG pathway maps showed that these genes were associated with aromatic compound biosynthetic process, heterocycle biosynthetic process, and mainly enriched on the pathways in cancer and PI3K-Akt signaling pathway.We identified 10 hub genes, 2 core modules and 19 seed genes in PPI network. Conclusion A total of 10 hub genes and 19 seed genes were screened, which may play potential roles in the tumorigenesis and progression of TNBC. This study provids a bioinformatic analysis reference for further research.

Key words: triple negative breast cancer, bioinformatics, GEO

摘要： 目的采用生物信息学分析,筛选与三阴性乳腺癌(triple-negative breast cancer, TNBC)发生发展相关的关键基因和通路。方法选取GEO (Gene Expression Omnibus)数据库中TNBC基因芯片数据集GSE76124及正常乳腺组织数据集GSE112825,应用R软件筛选差异表达基因。使用DAVID数据库对上述差异表达基因进行GO (Gene Ontology)功能分析及KEGG (Kyoto Encyclopedia of Genes and Genome)通路分析。应用STRING在线数据库和Cytoscape软件构建蛋白质相互作用(protein-protein interaction,PPI)网络,并筛选TNBC的hub genes、枢纽模块和seed genes。结果分析芯片数据,筛选得到1091个差异表达基因,GO和KEGG分析结果显示,差异表达基因与芳香类物质生物合成、杂环生物合成等过程有关,并富集在cancer通路、PI3K/AKT通路上。通过构建PPI网络筛选得到了10个hub genes、2个枢纽模块和19个seed genes。结论本研究筛选得到10个hub genes和19个seed genes,这些基因在TNBC的发生发展中可能存在潜在的作用,为下一步研究提供生物信息学分析参考。

关键词: 三阴性乳腺癌, 生物信息学, GEO

CLC Number:

R737.9

NIU Lin, LIU Lei, CHENG Lu-yang, XU Qian, CHEN Zhi-hong, QIAO Yue-bing. Screening Key Genes and Pathways in Triple-negative Breast Cancer by Bioinformatics Analysis[J]. Journal of Chengde Medical University, 2020, 37(5): 361-368.

钮淋, 刘镭, 程露阳, 许倩, 陈志宏, 乔跃兵. 基于生物信息学筛选三阴性乳腺癌关键基因和通路[J]. 承德医学院学报, 2020, 37(5): 361-368.

References

[1] 王宁,刘硕,杨雷,等. 2018全球癌症统计报告解读[J]. 肿瘤综合治疗电子杂志,2019, 5(01): 87-97.
[2] Karaayyaz M, Cristea S, Gillespie SM, et al.Unravelling subclonal heterogeneity and aggressive disease states in TNBC through single-cell RNA-seq[J]. Nat Commun, 2018, 9(1): 3588.
[3] Lee KL, Kuo YC, Ho YS, et al.Triple-Negative Breast Cancer: Current Understanding and Future Therapeutic Breakthrough Targeting Cancer Stemness[J]. Cancers (Basel), 2019,11(9): 1334.
[4] Bareche Y, Venet D, Ignatiadis M, et al.Unravelling triple-negative breast cancer molecular heterogeneity using an integrative multiomic analysis[J]. Ann Oncol, 2018, 29(4): 895-902.
[5] Burstein MD, Tsimelzon A, Poage GM, et al.Comprehensive genomic analysis identifies novel subtypes and targets of triple-negative breast cancer[J]. Clin Cancer Res, 2015, 21(7): 1688-1698.
[6] Santucci-Pereira J, Zeleniuch-Jacquotte A, Afanasyeva Y, et al.Genomic signature of parity in the breast of premenopausal women[J]. Breast Cancer Res, 2019, 21(1): 46.
[7] Kumar S, Wilkes DW, Samuel N, et al.Delta Np63-driven recruitment of myeloid-derived suppressor cells promotes metastasis in triple-negative breast cancer[J]. J Clin Invest, 2018, 128(11): 5095-5109.
[8] Zeng Y, Wang CL, Xian J, et al.Positive correlation between programmed death ligand-1 and p53 in triple-negative breast cancer[J]. Onco Targets Ther, 2019,12: 7193-7201.
[9] Yu S, Cai X, Wu C, et al.Targeting HSP90-HDAC6 Regulating Network Implicates Precision Treatment of Breast Cancer[J]. Int J Biol Sci, 2017, 13(4): 505-517.
[10] He Y, Jiang Z, Chen C, et al.Classification of triple-negative breast cancers based on Immunogenomic profiling[J]. J Exp Clin Cancer Res, 2018, 37(1): 327.
[11] Zhang QQ, Chen J, Zhou DL, et al.Dipalmitoylphosphatidic acid inhibits tumor growth in triple-negative breast cancer[J]. Int J Biol Sci, 2017,13(4): 471-479.
[12] Qian X, Song X, He Y, et al.CCNB2 overexpression is a poor prognostic biomarker in Chinese NSCLC patients[J]. Biomed Pharmacother, 2015, 74: 222-227.
[13] Shekhar R, Priyanka P, Kumar P, et al.The microRNAs miR-449a and miR-424 suppress osteosarcoma by targeting cyclin A2 expression[J]. J Biol Chem, 2019, 294(12): 4381-4400.
[14] Xie B, Wang S, Jiang N, et al.Cyclin B1/CDK1-regulated mitochondrial bioenergetics in cell cycle progression and tumor resistance[J]. Cancer Lett, 2019, 443: 56-66.
[15] Liu G, Zhao J, Pan B, et al.UBE2C overexpression in melanoma and its essential role in G2/M transition[J]. J Cancer, 2019,10(10): 2176-2184.
[16] Gluz O, Kolberg-Olberg-Liedtke C, Prat A, et al. Efficacy of deescalated chemotherapy according to PAM50 subtypes, immune and proliferation genes in triple-negative early breast cancer: Primary translational analysis of the WSG-ADAPT-TN trial[J]. Int J Cancer, 2020, 146(1): 262-271.
[17] Zheng H, Li X, Chen C, et al.Quantum dot-based immunofluorescent imaging and quantitative detection of TOP2A and prognostic value in triple-negative breast cancer[J]. Int J Nanomedicine, 2016, 11: 5519-5529.
[18] Fu X, Chen G, Cai ZD, et al.Overexpression of BUB1B contributes to progression of prostate cancer and predicts poor outcome in patients with prostate cancer[J]. Onco Targets Ther, 2016, 9: 2211-2220.
[19] Ma Q, Liu Y, Shang L, et al.The FOXM1/BUB1B signaling pathway is essential for the tumorigenicity and radioresistance of glioblastoma[J]. Oncol Rep, 2017, 38(6): 3367-3375.
[20] Meng QC, Wang HC, Song ZL, et al.Overexpression of NDC80 is correlated with prognosis of pancreatic cancer and regulates cell proliferation[J]. Am J Cancer Res, 2015, 5(5): 1730-1740.
[21] Bai J, Li Y, Zhang G.Cell cycle regulation and anticancer drug discovery[J]. Cancer Biol Med, 2017, 14(4): 348-362.
[22] von Wahlde MK, Hülsewig C, Ruckert C, et al. The anti-androgen drug dutasteride renders triple negative breast cancer cells more sensitive to chemotherapy via inhibition of HIF-1α-/VEGF-signaling[J]. Gynecol Endocrinol, 2015, 31(2): 160-164.
[23] Apaya MK, Hsiao PW, Yang YC, et al.Deregulating the CYP2C19/Epoxy-Eicosatrienoic Acid-Associated FABP4/FABP5 Signaling Network as a Therapeutic Approach for Metastatic Triple-Negative Breast Cancer[J]. Cancers (Basel), 2020, 12(1): 199.
[24] Xiao Y, Li Y, Tao H, et al.Integrin α5 down-regulation by miR-205 suppresses triple negative breast cancer stemness and metastasis by inhibiting the Src/Vav2/Rac1 pathway[J]. Cancer Lett, 2018, 433: 199-209.
[25] Scintu M, Vitale R, Prencipe M, et al.Genomic instability and increased expression of BUB1B and MAD2L1 genes in ductal breast carcinoma[J]. Cancer Lett, 2007, 254(2): 298-307.
[26] Dang SC, Qian XB, Jin W, et al.G-protein-signaling modulator 2 expression and role in a CD133+pancreatic cancer stem cell subset[J]. Onco Targets Ther, 2019, 12: 785-794.
[27] Zhang L, Li J, Lv X, et al.MID1-PP2A complex functions as new insights in human lung adenocarcinoma[J]. J Cancer Res Clin Oncol, 2018, 144(5): 855-864.
[28] Mo D, Li C, Liang J, et al.Low PBRM1 identifies tumor progression and poor prognosis in breast cancer[J]. Int J Clin Exp Pathol, 2015, 8(8): 9307-9313.
[29] Long R, Liu Z, Li J, et al.COL6A6 interacted with P4HA3 to suppress the growth and metastasis of pituitary adenoma via blocking PI3K-Akt pathway[J]. Aging (Albany NY), 2019, 11(20): 8845-8859.
[30] Ackermann A, Schrecker C, Bon D, et al.Downregulation of SPTAN1 is related to MLH1 deficiency and metastasis in colorectal cancer[J]. PLoS One, 2019, 14(3): e0213411.
[31] Li N, Xue W, Yuan H, et al.AKT-mediated stabilization of histone methyltransferase WHSC1 promotes prostate cancer metastasis[J].J Clin Invest, 2017, 127(4): 1284-1302.
[32] Yeom CJ, Zeng L, Goto Y, et al.LY6E: a conductor of malignant tumor growth through modulation of the PTEN/PI3K/Akt/HIF-1 axis[J]. Oncotarget, 2016, 7(40): 65837-65848.
[33] Yu SY, Wang YP, Chang JY, et al.Increased expression of MCM5 is significantly associated with aggressive progression and poor prognosis of oral squamous cell carcinoma[J]. J Oral Pathol Med, 2014, 43(5): 344-349.
[34] Zhou C, Sun J, Zheng Z, et al.High RPS11 level in hepatocellular carcinoma associates with poor prognosis after curative resection[J].Ann Transl Med, 2020, 8(7): 466.