The implication from RAS/RAF/ERK signaling pathway increased activation in epirubicin treated triple negative breast cancer.

{"sci_version": "1.2", "schema": "https://corpus.bntrg.co.uk/sci/1.0/sci.schema.json", "id": "pmid:29296238", "kind": "science-record", "revision": 8, "content_hash": "sha256:b9bbc780afb7f36e654c9c2d51aaeb62210c03e4abe53323663dce9b20d299d8", "created_at": "2026-11-01T15:40:30Z", "updated_at": "2026-11-01T21:59:39Z", "generator": {"name": "corpus-assay-engine", "run_id": "reading-sci-2026-11-01"}, "paper": {"state": "complete", "title": "The implication from RAS/RAF/ERK signaling pathway increased activation in epirubicin treated triple negative breast cancer.", "doi": "10.18632/oncotarget.22604", "pmid": "29296238", "authors": ["Jianbo Huang", "Qingqing Luo", "Yun Xiao", "Hongyuan Li", "Lingquan Kong", "Guosheng Ren"], "journal": "Oncotarget", "year": 2017, "abstract": "BACKGROUND: Triple negative breast cancer (TNBC) is not sensitive to RAS/RAF/ERK signaling pathway (ERK pathway) targeting therapy, due to the absence of excessive activation of ERK pathway. However, the kinase cascades might be activated after chemotherapy in TNBC. Here we aimed to predict whether ERK pathway targeting therapy could be used as an adjuvant therapy in TNBC.\nMETHODS: Within online GEO datasets (GSE43816 and GSE54326), gene set enrichment analysis (GSEA) was performed to detect molecular changes in epirubicin treated TNBC samples and cells, ERK pathway components and regulation genes changes were included.\nRESULTS: In epirubicin treated TNBC samples and cells, we found ERK pathway components (eg. MAPK13, MAP3K1, MAPK12, MAPK11 and MAPKAPK3) were obviously enriched, also, expression of ERK pathway positive regulation genes significantly increased (P<0.05) and negative regulation genes decreased (P<0.05) in epirubicin resistant cells. Moreover, phosphorylated ERK levels were significantly elevated in MDA-MB-231 cells after epirubicin treatment.\nCONCLUSION: ERK signaling pathway was more activated in epirubicin treated TNBC, possibly contributing to the epirubicin resistance in TNBC, it implicated that ERK pathway could be used as an novel candidate for targeting therapy in refractory and relapse TNBC.", "claims": [{"id": "claim-method", "statement": "GEO datasets GSE43816 and GSE54326 were downloaded from website (https://www.ncbi.nlm.nih.gov/), GSEA, enrichment map analysis and heat map were performed with R software. Statistical analysis was done using Student's t-test, variance analysis and/or non-parametric tests. For all the tests, P<0.05 was considered as statistical significance. All statistics were calculated by SPSS 13.0 or R software.", "kind": "methodological", "target": null, "evidence": [{"asset": "source:pmid:29296238", "locator": "sections[9] \"GEO datasets, GSEA, enrichment map analysis and heatmap\" paragraph 2", "quote": "GEO datasets GSE43816 and GSE54326 were downloaded from website (https://www.ncbi.nlm.nih.gov/), GSEA, enrichment map analysis and heat map were performed with R software."}, {"asset": "source:pmid:29296238", "locator": "sections[13] \"Statistics\" paragraph 2", "quote": "Statistical analysis was done using Student's t-test, variance analysis and/or non-parametric tests."}, {"asset": "source:pmid:29296238", "locator": "sections[13] \"Statistics\" paragraph 2", "quote": "For all the tests, P<0.05 was considered as statistical significance."}, {"asset": "source:pmid:29296238", "locator": "sections[13] \"Statistics\" paragraph 2", "quote": "All statistics were calculated by SPSS 13.0 or R software."}], "state": "complete"}, {"id": "claim-data-access", "statement": "Here we applied an online GEO dataset (GSE43816) for GSEA to discuss the molecular changes in epirubicin treated TNBC. This cohort study of 7 women with primary invasive TNBC were collected for tumor specimen before and after 4 cycles of NAC with epirubicine and cyclophosphamide, followed by 4 cycles of taxanes.", "kind": "methodological", "target": null, "evidence": [{"asset": "source:pmid:29296238", "locator": "sections[4] \"ERK pathway activation elevated in epirubicin treated TNBC samples\" paragraph 2", "quote": "Here we applied an online GEO dataset (GSE43816) for GSEA to discuss the molecular changes in epirubicin treated TNBC. This cohort study of 7 women with primary invasive TNBC were collected for tumor specimen before and after 4 cycles of NAC with epirubicine and cyclophosphamide, followed by 4 cycles of taxanes."}], "state": "complete"}, {"id": "claim-target-result", "statement": "Using gene set enrichment analysis of the online GEO datasets GSE43816 and GSE54326, the study found that ERK signaling became more activated in epirubicin-treated TNBC, with positive-regulation gene expression increased and negative-regulation gene expression decreased at P<0.05, suggesting a possible role in epirubicin resistance.", "kind": "quantitative", "target": {"value": 0.05, "unit": "p-value", "tolerance": null, "source": "In epirubicin treated TNBC samples and cells, we found ERK pathway components (eg. MAPK13, MAP3K1, MAPK12, MAPK11 and MAPKAPK3) were obviously enriched, also, expression of ERK pathway positive regulation genes significantly increased (P<0.05) and negative regulation genes decreased (P<0.05) in epirubicin resistant cells."}, "evidence": [{"asset": "source:pmid:29296238", "locator": "sections[0] \"Abstract\" paragraph 2", "quote": "Within online GEO datasets (GSE43816 and GSE54326), gene set enrichment analysis (GSEA) was performed to detect molecular changes in epirubicin treated TNBC samples and cells, ERK pathway components and regulation genes changes were included."}, {"asset": "source:pmid:29296238", "locator": "sections[0] \"Abstract\" paragraph 3", "quote": "In epirubicin treated TNBC samples and cells, we found ERK pathway components (eg. MAPK13, MAP3K1, MAPK12, MAPK11 and MAPKAPK3) were obviously enriched, also, expression of ERK pathway positive regulation genes significantly increased (P<0.05) and negative regulation genes decreased (P<0.05) in epirubicin resistant cells."}, {"asset": "source:pmid:29296238", "locator": "sections[0] \"Abstract\" paragraph 4", "quote": "ERK signaling pathway was more activated in epirubicin treated TNBC, possibly contributing to the epirubicin resistance in TNBC, it implicated that ERK pathway could be used as an novel candidate for targeting therapy in refractory and relapse TNBC."}], "state": "complete"}], "gaps": []}, "experiment": {"state": "partial", "objective": "Using gene set enrichment analysis of the online GEO datasets GSE43816 and GSE54326, the study found that ERK signaling became more activated in epirubicin-treated TNBC, with positive-regulation gene expression increased and negative-regulation gene expression decreased at P<0.05, suggesting a possible role in epirubicin resistance.", "steps": [{"id": "read_published_estimate", "order": 1, "name": "Read the published estimate from the source", "kind": "other", "state": "complete", "blocked_on": null, "description": "The claim, method and evidence span published with the source article.", "duration_hours": null, "parameters": {}, "inputs": ["source:pmid:29296238"], "outputs": ["the published estimate and its evidence"], "instruments": [], "reagents": []}, {"id": "obtain_source_data", "order": 2, "name": "Obtain the source data from the named repository", "kind": "data-preparation", "state": "complete", "blocked_on": null, "description": "The GEO series accession resolves and its sample accessions are listed. 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(July, 2017)", "structure": {"pmcid": "PMC5746140", "section_index": 3, "section_title": "A retrospective overview of ERK pathway inhibitors in cancer treatment", "row_count": 19, "column_count": 6}, "table": {"label": "Table 1", "caption": "Clinical trials evaluating RAS/RAF/ERK inhibitors, according to Clinical Trials.gov. (July, 2017)", "rows": [["Compound", "Combination", "Phase", "Tumor", "Results", "Author, Year"], ["Selumetinib (MEK1/2 inhibitor)", "-", "II", "Myeloma (36)", "The response rate (CR + PR) was 5.6% with a mean duration of response of 4.95 months and median progression-free survival time of 3.52 months. One patient had a very good partial response, 1 patient had a partial response, 17 patients had stable disease, 13 patients had progressive disease.", "Holkova B, 2016"], ["Vemurafenib (BRAF inhibitor)", "-", "II", "Leukemia (54)", "The overall response rates were 96% (25 of 26 patients who could be evaluated) after a median of 8 weeks in the Italian study and 100% (24 of 24) after a median of 12 weeks in the U.S. study. The rates of complete response were 35% (9 of 26 patients) and 42% (10 of 24) in the two trials, respectively.", "Tiacci E, 2015"], ["Selumetinib (MEK1/2 inhibitor)", "dacarbazine", "III", "Uveal melanoma (estimated 128)", "Ongoing", "Carvajal RD, 2015"], ["Trametinib (MEK1/2 inhibitor)", "-", "II", "NSCLC (86)", "10 (12%) patients had partial responses", "Blumenschein GR Jr, 2015"], ["Selumetinib (MEK1/2 inhibitor)", "irinotecan", "II", "Colorectal (31)", "3 patients (9.7 %) had partial response. 16 patients (51.6 %) had stable disease for ≥4 weeks, including three >1 year.", "Hochster HS, 2015"], ["Vemurafenib (BRAF inhibitor)", "", "II", "Papillary thyroid cancer (51)", "Partial responses were recorded in ten of 26 patients in cohort 1.", "Brose MS, 2016"], ["Trametinib (MEK inhibitor)", "Dabrafenib", "II", "Melanoma (23)", "Disease control rate was 45%, and median PFS was 13 weeks.", "Chen G, 2016"], ["Selumetinib (MEK1/2 inhibitor)", "", "II", "Endometrial cancer (54)", "Three (6%) patients had objective response (1 CR, 2 PR); 13 had SD as best response. The proportion of patients with 6-month EFS was 12%. Median EFS, progression-free and overall survival was 2.1, 2.3, and 8.5months, respectively.", "Coleman RL, 2015"], ["Trametinib (MEK inhibitor)", "Dabrafenib", "II", "colorectal cancer (43)", "Five (12%) achieved a partial response or better, including one (2%) complete response, with duration of response > 36 months; 24 patients (56%) achieved stable disease as best confirmed response.", "Corcoran RB, 2015"], ["Binimetinib (MEK inhibitor)", "", "III", "Melanoma (402)", "Median progression-free survival was 2·8 months in the binimetinib group and 1·5 months in the dacarbazine group.", "Dummer R, 2017"], ["Selumetinib (MEK inhibitor)", "temsirolimus", "II", "Soft-tissue sarcomas (71)", "There was no difference in PFS between the two arms for the overall cohort; an improved median PFS was observed in the combination arm (N = 11) over single agent (N = 10) in the prespecified leiomyosarcoma stratum. Four-month PFS rate was 50% with the combination vs 0% with selumetinib alone in the leiomyosarcoma cohort.", "Eroglu Z, 2015"], ["Selumetinib (MEK1/2 inhibitor)", "Erlotinib", "II", "Pancreatic Adenocarcinoma (46)", "Although no objective responses were observed, 19 patients (41%) showed evidence of stable disease for ≥6 weeks, and 13 of 34 patients (38%) had a CA19-9 decline ≥50%. Median progression-free survival was 1.9 months, with a median overall survival of 7.3 months.", "Ko AH, 2016"], ["Vemurafenib (BRAF inhibitor)", "II", "", "Colorectal (21)", "Of the 21 patients treated, one patient had a confirmed partial response and seven other patients had stable disease by RECIST criteria. Median progression- free survival was 2.1 months.", "Kopetz S, 2015"], ["Trametinib (MEK1/MEK2 inhibitor)", "", "III", "Melanoma (322)", "The intent-to-treat (ITT) analysis estimated a 28% reduction in the hazard of death with trametinib treatment for patients in the primary efficacy population. Adjustment analyses deemed plausible provided OS HR point estimates ranging from 0.48 to 0.53. Similar reductions in the HR were estimated for the first-line metastatic subgroup. Treatment with trametinib, compared with chemotherapy, significantly reduced the risk of death and risk of disease progression in patients with BRAF V600E/K mutation-positive advanced melanoma or MM.", "Latimer NR, 2016"], ["Trametinib (MEK inhibitors) Dabrafenib (BRAF inhibitor)", "", "II", "NSCLC(57)", "Thirty-six patients (63·2%) achieved an investigator-assessed overall response", "Planchard D, 2016"], ["Dabrafenib (BRAF inhibitor)", "", "II", "NSCLC(84)", "Twenty-six of the 78 previously treated patients achieved an investigator-assessed overall response (33%). Four of the six previously untreated patients had an objective response.", "Planchard D, 2016"], ["Dabrafenib (BRAF inhibitor) and Trametinib (MEK inhibitor)", "", "III", "Melanoma(704)", "The overall survival rate at 12 months was 72% in the combination-therapy group and 65% in the vemurafenib group. The prespecified interim stopping boundary was crossed, and the study was stopped for efficacy. Median progression-free survival was 11.4 months in the combination-therapy group and 7.3 months in the vemurafenib group. The objective response rate was 64% in the combination-therapy group and 51% in the vemurafenib group.", "Robert C, 2015"], ["Selumetinib (MEK 1/2 inhibitor)", "Fulvestrant", "II", "Breast(46)", "Recruitment was interrupted because the selumetinib-fulvestrant arm did not reach the pre-specified DCR. DCR was 23% in the selumetinib arm and 50%in the placebo arm. Median progression-free survival was 3.7months in the selumetinib arm and 5.6months in the placebo arm. Median time to treatment failure was 5.1 and 5.6 months, respectively.", "Zaman K, 2015"]], "row_count": 19, "column_count": 6, "numeric_cells": 60, "header_rows": 1, "locator": "section[3]/table-wrap[1]#T1"}}, {"id": "asset:table:pmid:29296238:2", "role": "table", "format": "jats-table", "media_type": "application/vnd.jats.table+json", "uri": null, "sha256": "sha256:0660b91d729d83dfec017089f710b4647e199c3d5df497ff248156524db95f90", "bytes": 857, "access": "open", "state": "verified", "reader": "read_table", "reader_status": "available", "identifier": "section[4]/table-wrap[1]#T2", "version": null, "note": "MAPK family gene enriched in ERKsignaling pathway after neoadjuvant chemotherapy", "structure": {"pmcid": "PMC5746140", "section_index": 4, "section_title": "ERK pathway activation elevated in epirubicin treated TNBC samples", "row_count": 9, "column_count": 5}, "table": {"label": "Table 2", "caption": "MAPK family gene enriched in ERKsignaling pathway after neoadjuvant chemotherapy", "rows": [["Probe", "Gene title", "Rank metric score", "Running ES", "Core enrichment"], ["KEGG_ MAPK signaling pathway"], ["MAPK10", "mitogen-activated protein kinase 10", "0.203", "0.1633", "Yes"], ["MAPK13", "mitogen-activated protein kinase 13", "0.113", "0.2426", "Yes"], ["MAPK11", "mitogen-activated protein kinase 11", "0.082", "0.2517", "Yes"], ["MAPKAPK3", "mitogen-activated protein kinase-activated protein kinase 3", "0.056", "0.2966", "Yes"], ["REACTOME_MAPK_TARGETS_NUCLEAR_EVENTS_MEDIATED_BY_MAP_KINASES"], ["MAPK10", "mitogen-activated protein kinase 10", "0.203", "0.4514", "Yes"], ["MAPK11", "mitogen-activated protein kinase 11", "0.082", "0.5460", "Yes"]], "row_count": 9, "column_count": 5, "numeric_cells": 23, "header_rows": 1, "locator": "section[4]/table-wrap[1]#T2"}}, {"id": "asset:table:pmid:29296238:3", "role": "table", "format": "jats-table", "media_type": "application/vnd.jats.table+json", "uri": null, "sha256": "sha256:a752fc96adcbcc36f5d4a737d581f2877a13e30960796501f39c2da9cc9a5ead", "bytes": 1798, "access": "open", "state": "verified", "reader": "read_table", "reader_status": "available", "identifier": "section[5]/table-wrap[1]#T3", "version": null, "note": "MAPK family gene enriched in ERK signaling pathway in epirubicin resistant MDA-MB-231 cells", "structure": {"pmcid": "PMC5746140", "section_index": 5, "section_title": "ERK pathway activation enhanced in epirubicin resistant TNBC cells", "row_count": 20, "column_count": 5}, "table": {"label": "Table 3", "caption": "MAPK family gene enriched in ERK signaling pathway in epirubicin resistant MDA-MB-231 cells", "rows": [["Probe", "Gene title", "Rank metric score", "Running ES", "Core enrichment"], ["KEGG_ MAPK signaling pathway"], ["MAPK8IP3", "mitogen-activated protein kinase 8 interacting protein 3", "2.315", "0.0635", "Yes"], ["MAPK13", "mitogen-activated protein kinase 13", "1.662", "0.1400", "Yes"], ["MAP3K14", "mitogen-activated protein kinase kinasekinase 14", "1.502", "0.1608", "Yes"], ["MAP3K1", "mitogen-activated protein kinase kinasekinase 1", "1.151", "0.2085", "Yes"], ["MAPKAPK3", "mitogen-activated protein kinase-activated protein kinase 3", "1.055", "0.2247", "Yes"], ["MAPK3", "mitogen-activated protein kinase 3", "1.039", "0.2289", "Yes"], ["MAPK12", "mitogen-activated protein kinase 12", "1.038", "0.2352", "Yes"], ["MAP4K2", "mitogen-activated protein kinase kinasekinasekinase 2", "1.006", "0.2440", "Yes"], ["MAP4K3", "mitogen-activated protein kinase kinasekinasekinase 3", "0.916", "0.2595", "Yes"], ["MAP2K6", "mitogen-activated protein kinase kinase 6", "0.909", "0.2636", "Yes"], ["MAPK11", "mitogen-activated protein kinase 11", "0.850", "0.2689", "Yes"], ["MAP3K8", "mitogen-activated protein kinase kinasekinase 8", "0.569", "0.2737", "Yes"], ["MAP2K3", "mitogen-activated protein kinase kinase 3", "0.499", "0.2806", "Yes"], ["REACTOME_ACTIVATED_TAK1_MEDIATES_P38_MAPK_ACTIVATION"], ["MAPKAPK3", 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