Bioinformatics analysis of hub genes for lapatinib resistance in breast cancer_CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY

Authors：

WU Shufei ^1,2 , TAN Qiao ² , ZHANG Chao ¹ , XIA Shusen ^1,2 , YI Pengsheng ^1,2 ,  HOU Lingmi ^1,2

1. Department of General Surgery 1, Yingshan Hospital, West China Hospital, Sichuan University, Nanchong, Sichuan 637000, P. R. China;
2. Academician (Expert) Workstation, Laboratory of Biological Targeting of Breast Cancer, Affiliated Hospital of North Sichuan Medical University, Nanchong, Sichuan 637000, P. R. China;

Corresponding author：

HOU Lingmi, Email: houlingmi@163.com

Keywords：

Breast cancer; bioinformatic; lapatinib resistance; hub gene

DOI：

10.7507/1007-9424.202108007

Video：

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Objective To screen the lapatinib resistance-related hub genes of breast cancer by bioinformatics initially in order to lay the foundation for further study. Methods We screened and downloaded the gene expression profile data of GSE16179 and GSE38376 from the gene expression omnibus (GEO), and used the limma package of R software to identify the differential expressed genes (DEGs) in breast cancer cells. Then we used the DAVID online website for pathway and function enrichment. With the usage of STRING and Cytoscape, the protein-protein interaction network (PPI) was constructed, and the plug-in app MCODE in Cytoscape was applied to screen hub genes. Then we performed the function enrichment and co-expression analysis of hub genes by DAVID and GeneMANIA. Kaplan-Meier Plotter was used to conduct survival analysis of hub genes. Results A total of 206 kinds of DEGs were screened, and there were 126 kinds of up-regulated genes and 80 kinds of down-regulated genes. DAVID results showed that DEGs were mainly enriched in the biological processes of extracellular space and extracellular region, including extracellular matrix organization, oxygen binding, integrin binding, cell adhesion, positive regulation of angiogenesis, Hippo signaling pathway, transforming growth factor-β signaling pathway and so on. PPI network visualized 74 nodes, the top 10 kinds of hub genes with high connectivity in the gene expression network were screened by MCODE. The Kaplan-Meier Plotter analysis confirmed that 6 of the 10 kinds of hub genes, including peroxisome proliferator activated receptor gamma, transforming growth factor beta receptor 2, tissue inhibitor of metalloproteinase 1, transforming growth factor beta induced, serpin family E member 1, and thrombospondin 1, were correlated with the prognosis of breast cancer patients. Conclusion This 6 kinds of genes may play a significant role in lapatinib resistance of breast cancer.

Citation： WU Shufei, TAN Qiao, ZHANG Chao, XIA Shusen, YI Pengsheng, HOU Lingmi. Bioinformatics analysis of hub genes for lapatinib resistance in breast cancer. CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY, 2022, 29(3): 337-344. doi: 10.7507/1007-9424.202108007 Copy

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2.	Fan L, Strasser-Weippl K, Li JJ, et al. Breast cancer in China. Lancet Oncol, 2014, 15(7): e279-e289. doi: 10.1016/S1470-2045(13)70567-9.
3.	李凡, 任国胜. 乳腺癌诊治现状与展望. 中国普外基础与临床杂志, 2019, 26(12): 1393-1397.
4.	D’Amato V, Raimondo L, Formisano L, et al. Mechanisms of lapatinib resistance in HER2-driven breast cancer. Cancer Treat Rev, 2015, 41(10): 877-883.
5.	Ruprecht B, Zaal EA, Zecha J, et al. Lapatinib resistance in breast cancer cells is accompanied by phosphorylation-mediated reprogramming of glycolysis. Cancer Res, 2017, 77(8): 1842-1853.
6.	Pondé N, Brandão M, El-Hachem G, et al. Treatment of advanced HER2-positive breast cancer: 2018 and beyond. Cancer Treat Rev, 2018, 67: 10-20.
7.	Liu L, Greger J, Shi H, et al. Novel mechanism of lapatinib resistance in HER2-positive breast tumor cells: activation of AXL. Cancer Res, 2009, 69(17): 6871-6878.
8.	Desany B, Zhang Z. Bioinformatics and cancer target discovery. Drug Discov Today, 2004, 9(18): 795-802.
9.	Behzadi P, Ranjbar R. DNA microarray technology and bioinformatic web services. Acta Microbiol Immunol Hung, 2019, 66(1): 19-30.
10.	Lehrke M, Lazar MA. The many faces of PPARgamma. Cell, 2005, 123(6): 993-999.
11.	Yousefnia S, Momenzadeh S, Seyed Forootan F, et al. The influence of peroxisome proliferator-activated receptor γ (PPARγ) ligands on cancer cell tumorigenicity. Gene, 2018, 649: 14-22.
12.	Michalik L, Desvergne B, Wahli W. Peroxisome-proliferator-activated receptors and cancers: complex stories. Nat Rev Cancer, 2004, 4(1): 61-70.
13.	Yang PB, Hou PP, Liu FY, et al. Blocking PPARγ interaction facilitates Nur77 interdiction of fatty acid uptake and suppresses breast cancer progression. Proc Natl Acad Sci U S A, 2020, 117(44): 27412-27422.
14.	杨宇钦. PPARG/FABP4信号通路介导乳腺癌增殖侵袭能力的体外研究. 广州: 南方医科大学, 2020.
15.	Clark DA, Coker R. Transforming growth factor-beta (TGF-beta). Int J Biochem Cell Biol, 1998, 30(3): 293-298.
16.	Caja L, Dituri F, Mancarella S, et al. TGF-β and the tissue microenvironment: relevance in fibrosis and cancer. Int J Mol Sci, 2018, 19(5): E1294. doi: 10.3390/ijms19051294.
17.	Dahmani A, Delisle JS. TGF-β in T cell biology: implications for cancer immunotherapy. Cancers (Basel), 2018, 10(6): E194. doi: 10.3390/cancers10060194.
18.	Li S, Liu M, Do MH, et al. Cancer immunotherapy via targeted TGF-β signalling blockade in T H cells. Nature, 2020, 587(7832): 121-125.
19.	Vitiello GAF, Amarante MK, Banin-Hirata BK, et al. Transforming growth factor beta receptorⅡ (TGFBR2) promoter region polymorphism in Brazilian breast cancer patients: association with susceptibility, clinicopathological features, and interaction with TGFB1 haplotypes. Breast Cancer Res Treat, 2019, 178(1): 207-219.
20.	Busch S, Sims AH, Stål O, et al. Loss of TGFβ receptor type 2 expression impairs estrogen response and confers tamoxifen resistance. Cancer Res, 2015, 75(7): 1457-1469.
21.	Rhee J, Han SW, Cha Y, et al. High serum TGF-α predicts poor response to lapatinib and capecitabine in HER2-positive breast cancer. Breast Cancer Res Treat, 2011, 125(1): 107-114.
22.	Lopez-Dee Z, Pidcock K, Gutierrez LS. Thrombospondin-1: multiple paths to inflammation. Mediators Inflamm, 2011, 2011: 296069. doi: 10.1155/2011/296069 .
23.	廖雪洪, 郑雄伟, 朱伟峰, 等. 乳腺癌中THBS-1表达及与EMT的相关性. 现代肿瘤医学, 2016, 24(20): 3219-3225.
24.	包楠丁, 贾永峰. THBS1在肿瘤中作用的研究进展. 标记免疫分析与临床, 2021, 28(4): 703-707.
25.	Shen J, Cao B, Wang Y, et al. Hippo component YAP promotes focal adhesion and tumour aggressiveness via transcriptionally activating THBS1/FAK signalling in breast cancer. J Exp Clin Cancer Res, 2018, 37(1): 175. doi: 10.1186/s13046-018-0850-z.
26.	Pal SK, Nguyen CT, Morita KI, et al. THBS1 is induced by TGFB1 in the cancer stroma and promotes invasion of oral squamous cell carcinoma. J Oral Pathol Med, 2016, 45(10): 730-739.
27.	Murphy G. Tissue inhibitors of metalloproteinases. Genome Biol, 2011, 12(11): 233. doi: 10.1186/gb-2011-12-11-233.
28.	樊嵘, 金冶宁. TIMP-1在乳腺癌中的作用机制和临床意义. 现代肿瘤医学, 2009, 17(1): 154-158.
29.	Hekmat O, Munk S, Fogh L, et al. TIMP-1 increases expression and phosphorylation of proteins associated with drug resistance in breast cancer cells. J Proteome Res, 2013, 12(9): 4136-4151.
30.	Ho D, Huang J, Chapman JW, et al. Impact of serum HER2, TIMP-1,and CAIX on outcome for HER2⁺ metastatic breast cancer patients: CCTG MA. 31 (lapatinib vs. trastuzumab). Breast Cancer Res Treat, 2017, 164(3): 571-580.
31.	Li S, Wei X, He J, et al. Plasminogen activator inhibitor-1 in cancer research. Biomed Pharmacother, 2018, 105: 83-94.
32.	Ghosh AK, Vaughan DE. PAI-1 in tissue fibrosis. J Cell Physiol, 2012, 227(2): 493-507.
33.	Duffy MJ, Harbeck N, Nap M, et al. Clinical use of biomarkers in breast cancer: updated guidelines from the European Group on Tumor Markers (EGTM). Eur J Cancer, 2017, 75: 284-298.
34.	Barzaman K, Karami J, Zarei Z, et al. Breast cancer: biology, biomarkers, and treatments. Int Immunopharmacol, 2020, 84: 106535. doi: 10.1016/j.intimp.2020.106535.
35.	Duffy MJ, McGowan PM, Harbeck N, et al. uPA and PAI-1 as biomarkers in breast cancer: validated for clinical use in level-of-evidence-1 studies. Breast Cancer Res, 2014, 16(4): 428. doi: 10.1186/s13058-014-0428-4.

1. DeSantis CE, Ma J, Gaudet MM, et al. Breast cancer statistics, 2019. CA Cancer J Clin, 2019, 69(6): 438-451.
2. Fan L, Strasser-Weippl K, Li JJ, et al. Breast cancer in China. Lancet Oncol, 2014, 15(7): e279-e289. doi: 10.1016/S1470-2045(13)70567-9.
3. 李凡, 任国胜. 乳腺癌诊治现状与展望. 中国普外基础与临床杂志, 2019, 26(12): 1393-1397.
4. D’Amato V, Raimondo L, Formisano L, et al. Mechanisms of lapatinib resistance in HER2-driven breast cancer. Cancer Treat Rev, 2015, 41(10): 877-883.
5. Ruprecht B, Zaal EA, Zecha J, et al. Lapatinib resistance in breast cancer cells is accompanied by phosphorylation-mediated reprogramming of glycolysis. Cancer Res, 2017, 77(8): 1842-1853.
6. Pondé N, Brandão M, El-Hachem G, et al. Treatment of advanced HER2-positive breast cancer: 2018 and beyond. Cancer Treat Rev, 2018, 67: 10-20.
7. Liu L, Greger J, Shi H, et al. Novel mechanism of lapatinib resistance in HER2-positive breast tumor cells: activation of AXL. Cancer Res, 2009, 69(17): 6871-6878.
8. Desany B, Zhang Z. Bioinformatics and cancer target discovery. Drug Discov Today, 2004, 9(18): 795-802.
9. Behzadi P, Ranjbar R. DNA microarray technology and bioinformatic web services. Acta Microbiol Immunol Hung, 2019, 66(1): 19-30.
10. Lehrke M, Lazar MA. The many faces of PPARgamma. Cell, 2005, 123(6): 993-999.
11. Yousefnia S, Momenzadeh S, Seyed Forootan F, et al. The influence of peroxisome proliferator-activated receptor γ (PPARγ) ligands on cancer cell tumorigenicity. Gene, 2018, 649: 14-22.
12. Michalik L, Desvergne B, Wahli W. Peroxisome-proliferator-activated receptors and cancers: complex stories. Nat Rev Cancer, 2004, 4(1): 61-70.
13. Yang PB, Hou PP, Liu FY, et al. Blocking PPARγ interaction facilitates Nur77 interdiction of fatty acid uptake and suppresses breast cancer progression. Proc Natl Acad Sci U S A, 2020, 117(44): 27412-27422.
14. 杨宇钦. PPARG/FABP4信号通路介导乳腺癌增殖侵袭能力的体外研究. 广州: 南方医科大学, 2020.
15. Clark DA, Coker R. Transforming growth factor-beta (TGF-beta). Int J Biochem Cell Biol, 1998, 30(3): 293-298.
16. Caja L, Dituri F, Mancarella S, et al. TGF-β and the tissue microenvironment: relevance in fibrosis and cancer. Int J Mol Sci, 2018, 19(5): E1294. doi: 10.3390/ijms19051294.
17. Dahmani A, Delisle JS. TGF-β in T cell biology: implications for cancer immunotherapy. Cancers (Basel), 2018, 10(6): E194. doi: 10.3390/cancers10060194.
18. Li S, Liu M, Do MH, et al. Cancer immunotherapy via targeted TGF-β signalling blockade in T H cells. Nature, 2020, 587(7832): 121-125.
19. Vitiello GAF, Amarante MK, Banin-Hirata BK, et al. Transforming growth factor beta receptorⅡ (TGFBR2) promoter region polymorphism in Brazilian breast cancer patients: association with susceptibility, clinicopathological features, and interaction with TGFB1 haplotypes. Breast Cancer Res Treat, 2019, 178(1): 207-219.
20. Busch S, Sims AH, Stål O, et al. Loss of TGFβ receptor type 2 expression impairs estrogen response and confers tamoxifen resistance. Cancer Res, 2015, 75(7): 1457-1469.
21. Rhee J, Han SW, Cha Y, et al. High serum TGF-α predicts poor response to lapatinib and capecitabine in HER2-positive breast cancer. Breast Cancer Res Treat, 2011, 125(1): 107-114.
22. Lopez-Dee Z, Pidcock K, Gutierrez LS. Thrombospondin-1: multiple paths to inflammation. Mediators Inflamm, 2011, 2011: 296069. doi: 10.1155/2011/296069 .
23. 廖雪洪, 郑雄伟, 朱伟峰, 等. 乳腺癌中THBS-1表达及与EMT的相关性. 现代肿瘤医学, 2016, 24(20): 3219-3225.
24. 包楠丁, 贾永峰. THBS1在肿瘤中作用的研究进展. 标记免疫分析与临床, 2021, 28(4): 703-707.
25. Shen J, Cao B, Wang Y, et al. Hippo component YAP promotes focal adhesion and tumour aggressiveness via transcriptionally activating THBS1/FAK signalling in breast cancer. J Exp Clin Cancer Res, 2018, 37(1): 175. doi: 10.1186/s13046-018-0850-z.
26. Pal SK, Nguyen CT, Morita KI, et al. THBS1 is induced by TGFB1 in the cancer stroma and promotes invasion of oral squamous cell carcinoma. J Oral Pathol Med, 2016, 45(10): 730-739.
27. Murphy G. Tissue inhibitors of metalloproteinases. Genome Biol, 2011, 12(11): 233. doi: 10.1186/gb-2011-12-11-233.
28. 樊嵘, 金冶宁. TIMP-1在乳腺癌中的作用机制和临床意义. 现代肿瘤医学, 2009, 17(1): 154-158.
29. Hekmat O, Munk S, Fogh L, et al. TIMP-1 increases expression and phosphorylation of proteins associated with drug resistance in breast cancer cells. J Proteome Res, 2013, 12(9): 4136-4151.
30. Ho D, Huang J, Chapman JW, et al. Impact of serum HER2, TIMP-1,and CAIX on outcome for HER2⁺ metastatic breast cancer patients: CCTG MA. 31 (lapatinib vs. trastuzumab). Breast Cancer Res Treat, 2017, 164(3): 571-580.
31. Li S, Wei X, He J, et al. Plasminogen activator inhibitor-1 in cancer research. Biomed Pharmacother, 2018, 105: 83-94.
32. Ghosh AK, Vaughan DE. PAI-1 in tissue fibrosis. J Cell Physiol, 2012, 227(2): 493-507.
33. Duffy MJ, Harbeck N, Nap M, et al. Clinical use of biomarkers in breast cancer: updated guidelines from the European Group on Tumor Markers (EGTM). Eur J Cancer, 2017, 75: 284-298.
34. Barzaman K, Karami J, Zarei Z, et al. Breast cancer: biology, biomarkers, and treatments. Int Immunopharmacol, 2020, 84: 106535. doi: 10.1016/j.intimp.2020.106535.
35. Duffy MJ, McGowan PM, Harbeck N, et al. uPA and PAI-1 as biomarkers in breast cancer: validated for clinical use in level-of-evidence-1 studies. Breast Cancer Res, 2014, 16(4): 428. doi: 10.1186/s13058-014-0428-4.

CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY

Bioinformatics analysis of hub genes for lapatinib resistance in breast cancer

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