title: Identification of novel therapeutic target genes in acquired lapatinib-resistant breast cancer by integrative meta-analysis.
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.
authors.affiliation: Department of Biochemistry, School of Medicine, Konkuk University, Seoul, 143-701, Republic of Korea.
authors.forename: Young Seok
authors.initials: YS
authors.lastname: Lee
authors.affiliation: Plant Genomics Laboratory, Department of Applied Plant Science, Kangwon National University, Chuncheon, Republic of Korea.
authors.forename: Sun Goo
authors.initials: SG
authors.lastname: Hwang
authors.affiliation: Department of Biochemistry, School of Medicine, Konkuk University, Seoul, 143-701, Republic of Korea.
authors.forename: Jin Ki
authors.initials: JK
authors.lastname: Kim
authors.affiliation: Department of Plastic and Reconstructive Surgery, College of Medicine, Yonsei University, Seoul, Republic of Korea.
authors.forename: Tae Hwan
authors.initials: TH
authors.lastname: Park
authors.affiliation: Department of Biochemistry, School of Medicine, Konkuk University, Seoul, 143-701, Republic of Korea.
authors.forename: Young Rae
authors.initials: YR
authors.lastname: Kim
authors.affiliation: Department of Biochemistry, School of Medicine, Konkuk University, Seoul, 143-701, Republic of Korea.
authors.forename: Ho Sung
authors.initials: HS
authors.lastname: Myeong
authors.affiliation: Department of Biochemistry, School of Medicine, Konkuk University, Seoul, 143-701, Republic of Korea.
authors.forename: Jong Duck
authors.initials: JD
authors.lastname: Choi
authors.affiliation: School of Korean Medicine, Pusan National University, Yangsan, Republic of Korea.
authors.forename: Kang
authors.initials: K
authors.lastname: Kwon
authors.affiliation: Plant Genomics Laboratory, Department of Applied Plant Science, Kangwon National University, Chuncheon, Republic of Korea.
authors.forename: Cheol Seong
authors.initials: CS
authors.lastname: Jang
authors.affiliation: Department of Biochemistry, School of Medicine, Konkuk University, Seoul, 143-701, Republic of Korea.
authors.forename: Young Tae
authors.initials: YT
authors.lastname: Ro
authors.affiliation: Department of Biochemistry, School of Medicine, Konkuk University, Seoul, 143-701, Republic of Korea.
authors.forename: Yun Hee
authors.initials: YH
authors.lastname: Noh
authors.affiliation: Department of Biochemistry, School of Medicine, Konkuk University, Seoul, 143-701, Republic of Korea. palelamp@kku.ac.kr.
authors.forename: Sung Young
authors.initials: SY
authors.lastname: Kim
mesh_terms: D000970:Antineoplastic Agents / Q000627:therapeutic use; D001943:Breast Neoplasms / Q000188:drug therapy / Q000235:genetics*; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D005260:Female; D020869:Gene Expression Profiling; D006801:Humans; D000077341:Lapatinib; D020411:Oligonucleotide Array Sequence Analysis; D060066:Protein Interaction Maps; D011799:Quinazolines / Q000627:therapeutic use
chemical_list: D000970:Antineoplastic Agents; D011799:Quinazolines; D000077341:Lapatinib
keywords: Acquired lapatinib resistance; Breast cancer; Differentially expressed genes; Meta-analysis; Microarray