Tumor Biology

, Volume 37, Issue 2, pp 2285–2297 | Cite as

Identification of novel therapeutic target genes in acquired lapatinib-resistant breast cancer by integrative meta-analysis

  • Young Seok Lee
  • Sun Goo Hwang
  • Jin Ki Kim
  • Tae Hwan Park
  • Young Rae Kim
  • Ho Sung Myeong
  • Jong Duck Choi
  • Kang Kwon
  • Cheol Seong Jang
  • Young Tae Ro
  • Yun Hee Noh
  • Sung Young Kim
Article

Abstract

Acquired resistance to lapatinib is a highly problematic clinical barrier that has to be overcome for a successful cancer treatment. Despite efforts to determine the mechanisms underlying acquired lapatinib resistance (ALR), no definitive genetic factors have been reported to be solely responsible for the acquired resistance in breast cancer. Therefore, we performed a cross-platform meta-analysis of three publically available microarray datasets related to breast cancer with ALR, using the R-based RankProd package. From the meta-analysis, we were able to identify a total of 990 differentially expressed genes (DEGs, 406 upregulated, 584 downregulated) that are potentially associated with ALR. Gene ontology (GO) function and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis of the DEGs showed that “response to organic substance” and “p53 signaling pathway” may be largely involved in ALR process. Of these, many of the top 50 upregulated and downregulated DEGs were found in oncogenesis of various tumors and cancers. For the top 50 DEGs, we constructed the gene coexpression and protein–protein interaction networks from a huge database of well-known molecular interactions. By integrative analysis of two systemic networks, we condensed the total number of DEGs to six common genes (LGALS1, PRSS23, PTRF, FHL2, TOB1, and SOCS2). Furthermore, these genes were confirmed in functional module eigens obtained from the weighted gene correlation network analysis of total DEGs in the microarray datasets (“GSE16179” and “GSE52707”). Our integrative meta-analysis could provide a comprehensive perspective into complex mechanisms underlying ALR in breast cancer and a theoretical support for further chemotherapeutic studies.

Keywords

Meta-analysis Microarray Differentially expressed genes Breast cancer Acquired lapatinib resistance 

Notes

Acknowledgments

This study was supported by the National Research Foundation of Korea Grant funded by the Korean Government (NRF-2013R1A1A1075999).

Conflicts of interest

None

Supplementary material

13277_2015_4033_MOESM1_ESM.docx (1.1 mb)
ESM 1 (DOCX 1.04 mb)
13277_2015_4033_MOESM2_ESM.xlsx (875 kb)
ESM 2 (XLSX 875 kb)

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Copyright information

© International Society of Oncology and BioMarkers (ISOBM) 2015

Authors and Affiliations

  • Young Seok Lee
    • 1
  • Sun Goo Hwang
    • 2
  • Jin Ki Kim
    • 1
  • Tae Hwan Park
    • 3
  • Young Rae Kim
    • 1
  • Ho Sung Myeong
    • 1
  • Jong Duck Choi
    • 1
  • Kang Kwon
    • 4
  • Cheol Seong Jang
    • 2
  • Young Tae Ro
    • 1
  • Yun Hee Noh
    • 1
  • Sung Young Kim
    • 1
  1. 1.Department of Biochemistry, School of MedicineKonkuk UniversitySeoulRepublic of Korea
  2. 2.Plant Genomics Laboratory, Department of Applied Plant ScienceKangwon National UniversityChuncheonRepublic of Korea
  3. 3.Department of Plastic and Reconstructive Surgery, College of MedicineYonsei UniversitySeoulRepublic of Korea
  4. 4.School of Korean MedicinePusan National UniversityYangsanRepublic of Korea

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