PMC:4307189 / 26978-37229 JSONTXT

{"target":"https://pubannotation.org/docs/sourcedb/PMC/sourceid/4307189","sourcedb":"PMC","sourceid":"4307189","source_url":"https://www.ncbi.nlm.nih.gov/pmc/4307189","text":"Netwalker analyses\nWe conducted further analyses using Netwalker, a network analysis suite for functional genomics [36]. In this analysis, we observed the changes in GE values for each gene in the identified list of potential cross-talks. This was to verify our expectation that, since lapatinib is an EGFR/ErbB inhibitor, both genes involved in drug-resistant cross-talks should be up-regulated in resistant conditions compared to parental conditions, which may imply that the activation of other compensatory signaling pathways in resistant conditions can play a role in acquired resistance to inhibitors by activating the targeted pathway(s) [1,17]. Therefore, for all 67 genes involved in the above sets of 104, 188 and 299 drug-resistant cross-talks from Reactome, KEGG and WikiPathway, respectively, we made a heatmap image of GE values from both conditions (parental and resistant) (Figure 3A). For both resistant and parental conditions, we first averaged the gene expression values from the three samples corresponding to the three treatment conditions. Then these averaged gene expression values were transformed into z-scores (zero mean, unit standard deviation) and each z-score was normalized with the maximum of the absolute values of the z-scores across that particular gene. We observed that in 28 of these 67 genes (involved in 168 cross-talks), gene expression in one or more resistant conditions (0, 0.1 μM and 1 μM of lapatinib) was up-regulated relative to all the parental conditions (0, 0.1 μM and 1 μM of lapatinib) (Figure 3B) which may signify the insensitivity of these genes to inhibitors under resistant conditions. Note for Figure 3B only those genes are depicted for which both genes in some identified cross-talk had average GE values at resistant conditions greater than the average GE values at parental conditions.\nFigure 2 Network view of (A) 104, (B) 188, and (C) 299 putative drug-resistant cross-talks between pathways using Reactome, KEGG, and WikiPathway pathway databases in Breast Cancer Cell-line: SKBR3 (GSE38376). Nodes are genes, and the edges are the cross-talks. Note, all the cross-talks here possess posterior probabilities of appearing in resistant network ≥ 0.5 and Odds Ratio ≥ 10.0, which means the posterior probabilities of that cross-talk for appearing in parental network is ≤ 0.05.\nFigure 3 Heatmap of genes in putative drug-resistant cross-talks in breast cancer cell-line: SKBR3 (GSE38376). Heatmap image of comparative gene expression changes of parental and resistant conditions in (A) all 67 genes in all 104, 188 and 299 putative drug-resistant cross-talks using signaling pathways from Reactome, KEGG and WikiPathway database, respectively, and (B) 28 selected genes based on their differential regulation. Here, for each gene, the expression value at each of the 6 conditions (3 parental conditions, and 3 resistant conditions) is the average value of 3 sample patients [17]. For each gene, these 6 expression values (each of them is the average of 3 samples) were transformed into z-scores (zero mean, unit standard deviation) and each z-score was normalized with the maximum absolute value of the z-scores across that particular gene. Note, (B) includes only those genes which belonged to gene-pairs for which the average of GE values at resistant conditions was greater than the average of GE values at parental conditions. For both (A) and (B), red and green bars indicate up-regulation and down-regulation, respectively.\nTable 1 Primary findings from the analyses using signaling pathways from Reactome, KEGG and WikiPathway in breast cancer cell-line: SKBR3 (GSE38376)\nPathway # of signaling Pathway of All Distinct All putative Distinct # of other\nsource pathways interest Cross-talks gene-pairs § drug-resistant gene-pairs ¶ signaling\nof interest cross-talks pathways\nREACTOME 23 EGFR 1,083 841 104 97 13\nKEGG 35 ErbB 2,179 1,050 188 99 26\nWikiPathway 63 ErbB 3,084 876 299 96 51\n¶Number of distinct gene-pairs involved in all EGFR/ErbB cross-talks with all other signaling pathways; §Number of distinct gene-pairs commonly involved in all EGFR/ErbB cross-talks and drug resistance.\nFor these 28 selected genes (168 cross-talks), we observed the relative changes in GE values (parental vs resistant conditions) in their candidate signaling pathways. First we analyzed EGFR signaling pathway from Reactome and found that many of the constituent genes were up-regulated in one (or more) resistant conditions whereas in all of their corresponding parental conditions they were down-regulated (Additional file 1: Figure S1). These 168 selected cross-talks associated EGFR (or ErbB) signaling pathways with 6 other signaling pathways that were found in at least two different pathway analyses (i.e. Reactome and KEGG, or KEGG and WikiPathway, or Reactome and WikiPathway). In those 6 other signaling pathways, we also observed a similar phenomenon as above (Additional file 1: Figure S1). These 6 signaling pathways are Notch signaling (in Reactome, KEGG and WikiPathway), Wnt signaling (in Reactome, KEGG and WikiPathway), insulin receptor/IGF1R signaling (in Reactome and WikiPathway), GPCR signaling (in Reactome and WikiPathway), hedgehog (in KEGG and WikiPathway), and TGF- β receptor signaling (in Reactome and WikiPathway). Again, for many of the constituent genes of these 6 signaling pathways, expression was up-regulated in at least one of the resistant conditions whereas in all the corresponding parental conditions they were down-regulated. Primary findings regarding these 168 selected drug-resistant cross-talks are listed in Additional file 9: Table S8, and the top 50 of those 168 cross-talks (based on sorted Odds ratio) are shown in Table 2.\nTable 2 Description of top 50 (based on sorted Odds ratio) cross-talks among all 168 potential drug-resistant cross-talks between EGFR/ErbB signaling and other pathways from all the analyses using Reactome, KEGG and WikiPathway databases in GSE38376\ngene i ::gene j EGFR/ErbB :: PrYijR=1 PrYijP=1 Odds ratio Avg GEiP : Avg GEiR :\nSignaling pathway j Avg GEjP Avg GEjR\nAKT2::MAML2 §,¶ Notch signaling 0.5 0.03 16.67 87.71::76.59 96.84::78.6\nMDM2::APC §,$ Wnt signaling 0.5 0.03 16.67 76.33::82.43 77.9::86.76\nKIT::CDC73 § Wnt signaling 0.5 0.03 16.67 82.14::104.01 82.68::110.88\nMDM2::CDC73 § Wnt signaling 0.5 0.03 16.67 76.33::104.01 77.9::110.88\nKIT::GNAQ § GPCR signaling 0.5 0.03 16.67 82.14::130 82.68::139.33\nMDM2::GNAQ §,$ GPCR signaling 0.5 0.03 16.67 76.33::130 77.9::139.33\nKIT::TSHR § GPCR signaling 0.5 0.03 16.67 82.14::71.32 82.68::71.66\nMDM2::TSHR § GPCR signaling 0.5 0.03 16.67 76.33::71.32 77.9::71.66\nAKT2::APC ¶ Wnt signaling 0.5 0.03 16.67 87.71::82.43 96.84::86.76\nAKT2::APC ¶ Hippo signaling 0.5 0.03 16.67 87.71::82.43 96.84::86.76\nAKT2::CDH1 ¶ Hippo signaling 0.5 0.03 16.67 87.71::74.2 96.84::79.8\nAKT2::GNAQ ¶ Gnrh signaling 0.5 0.03 16.67 87.71::130 96.84::139.33\nAKT2::GNAQ ¶ Calcium signaling 0.5 0.03 16.67 87.71::130 96.84::139.33\nAKT2::MDM2 ¶ p53 signaling 0.5 0.03 16.67 87.71::76.33 96.84::77.9\nMDM2::AKT2 $ Regulation of toll-like 0.5 0.03 16.67 76.33::87.71 77.9::96.84\nreceptor signaling\nMDM2::AKT2 $ insulin signaling 0.5 0.03 16.67 76.33::87.71 77.9::96.84\nMDM2::AKT2 $ RANKL/RANK signaling 0.5 0.03 16.67 76.33::87.71 77.9::96.84\nMDM2::AKT2 $ AMPK signaling 0.5 0.03 16.67 76.33::87.71 77.9::96.84\nMDM2::AKT2 $ MAPK signaling 0.5 0.03 16.67 76.33::87.71 77.9::96.84\nMDM2::AKT2 $ Tweak signaling 0.5 0.03 16.67 76.33::87.71 77.9::96.84\nMDM2::AKT2 $ Toll-like 0.5 0.03 16.67 76.33::87.71 77.9::96.84\nreceptor signaling\nMDM2::APC $ BDNF signaling 0.5 0.03 16.67 76.33::82.43 77.9::86.76\nMDM2::APC $ Wnt signaling Netpath 0.5 0.03 16.67 76.33::82.43 77.9::86.76\nMDM2::APC $ Wnt signaling 0.5 0.03 16.67 76.33::82.43 77.9::86.76\nand Pluripotency\nMDM2::COL1A1 $ Nanoparticle-mediated 0.5 0.03 16.67 76.33::91.44 77.9::102.54\nactivation of receptor\nsignaling\nMDM2::COL1A1 $ Osteoblast signaling 0.5 0.03 16.67 76.33::91.44 77.9::102.54\nMDM2::GNAQ $ TSH signaling 0.5 0.03 16.67 76.33::130 77.9::139.33\nMDM2::GNAQ $ Serotonin Receptor 2 0.5 0.03 16.67 76.33::130 77.9::139.33\nand STAT3 signaling\nMDM2::GNAQ $ Serotonin Receptor 2 0.5 0.03 16.67 76.33::130 77.9::139.33\nand ELK-SRF/GATA4\nsignaling\nMDM2::ITK $ T-Cell Receptor and 0.5 0.03 16.67 76.33::89.86 77.9::93.27\nCo-stimulatory signaling\nMDM2::ITK $ Tcr signaling 0.5 0.03 16.67 76.33::89.86 77.9::93.27\nMDM2::KIT $ Kit receptor signaling 0.5 0.03 16.67 76.33::82.14 77.9::82.68\nMDM2::PAX5 $ ID signaling 0.5 0.03 16.67 76.33::68.91 77.9::71.02\nMDM2::TSHR $ TSH signaling 0.5 0.03 16.67 76.33::71.32 77.9::71.66\nAKT2::TP53 § Notch signaling 0.5 0.04 12.5 87.71::128.73 96.84::155.09\nKIT::APC § Wnt signaling 0.5 0.04 12.5 82.14::82.43 82.68::86.76\nKIT::MAML2 § Notch signaling 0.5 0.04 12.5 82.14::76.59 82.68::78.6\nKIT::STK11 § IGF1R signaling 0.5 0.04 12.5 82.14::71.97 82.68::74.95\nKIT::STK11 § insulin receptor signaling 0.5 0.04 12.5 82.14::71.97 82.68::74.95\nKIT::TP53 § Notch signaling 0.5 0.04 12.5 82.14::128.73 82.68::155.09\nMDM2::MAML2 §,$ Notch signaling 0.5 0.04 12.5 76.33::76.59 77.9::78.6\nMDM2::STK11 § IGF1R signaling 0.5 0.04 12.5 76.33::71.97 77.9::74.95\nMDM2::STK11 § insulin receptor signaling 0.5 0.04 12.5 76.33::71.97 77.9::74.95\nMDM2::TP53 § Notch signaling 0.5 0.04 12.5 76.33::128.73 77.9::155.09\nAKT2::GNAS ¶ Gnrh signaling 0.5 0.04 12.5 87.71::5465.46 96.84::6212.43\nAKT2::GNAS ¶ Calcium signaling 0.5 0.04 12.5 87.71::5465.46 96.84::6212.43\nAKT2::NF2 ¶ Hippo signaling 0.5 0.04 12.5 87.71::85.75 96.84::87.36\nAKT2::TP53 ¶ P53 signaling 0.5 0.04 12.5 87.71::128.73 96.84::155.09\nAKT2::TP53 ¶ Wnt signaling 0.5 0.04 12.5 87.71::128.73 96.84::155.09\nCBL::CDH1 ¶ RAP1 signaling 0.5 0.04 12.5 194.46::74.2 208.45::79.8\nCross-talks found using signaling pathways from §Reactome, ¶KEGG, and $xx−xxWikiPathway Databases; Pathway j is the pathway containing gene j; PrYijR=1 and PrYijP=1 are the posterior probabilities of gene i:gene j in Resistant and Parental networks, respectively; AvgGEiP is the average GE value of all Parental conditions (each of which is an average of 3 samples) for gene i, AvgGEiR is similar but with Resistant conditions, and others are likewise 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