Identification of genes responsible for RelA-dependent proliferation arrest in human mammary epithelial cells conditionally expressing RelA.

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Semi-quantitative immunohistochemistry of primary breast tumors using antibodies to RelA, the pleiotropic NF-kB factor, and Ki67 revealed a negative correlation between RelA levels and Ki67-index among ER +/HER2 - tumors [1]. Similarly, expression of AURKA, a marker for proliferation, negatively correlates with expression of NFKBIA, a surrogate for RelA expression and activity, in ER +/HER2 - tumors analyzed by The Cancer Genome Atlas [2], [3], [4]. Furthermore, conditional expression of RelA using a Tetracycline-inducible system in Human Mammary Epithelial Cells (HRA cells) caused proliferation arrest while withdrawal of Doxycycline (Dox) and suppression of RelA expression in arrested cells restored cell cycle progression [1]. To identify genes responsible for the negative relationship between RelA levels and proliferation, we performed genome-wide gene expression analysis of HRA cells under the following conditions: RelA un-induced, No Dox (ND); Dox induced for 24 h; Dox induced for 72 h; Dox induced for 24 h then Dox withdrawn for 48 h. The expression data was submitted to Gene Expression Ominibus (GEO) and the accession number is GSE65040. Analysis of the data identified cross-talk between basal RelA activity and the Interferon pathway mediated by IRF1, a target of RelA [5]. Activation of the Interferon pathway lead to down-regulation of CDK4 expression resulting in RB1 hypo-phosphorylation and suppression of cell cycle progression. The tumor-suppressor activity of NF-kB, specifically RelA, may stem from cross-talk with the Interferon pathway.", "claims": [{"id": "claim-method", "statement": "Differentially expressed genes between pairs of samples were identified using LIMMA implemented in MEV [10].", "kind": "methodological", "target": null, "evidence": [{"asset": "source:pmid:26981373", "locator": "sections[6] \"Gene expression analysis\" paragraph 2", "quote": "Differentially expressed genes between pairs of samples were identified using LIMMA implemented in MEV [10]."}], "state": "complete"}, {"id": "claim-data-access", "statement": "Direct link to gene expression data deposited in Gene Expression Omnibus (GEO)\nhttp://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE65040.", "kind": "methodological", "target": null, "evidence": [{"asset": "source:pmid:26981373", "locator": "sections[2] \"Direct link to gene expression data deposited in Gene Expression Omnibus (GEO)\" paragraphs 1-2", "quote": "Direct link to gene expression data deposited in Gene Expression Omnibus (GEO)\nhttp://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE65040."}], "state": "complete"}, {"id": "claim-target-result", "statement": "Genome-wide gene-expression analysis identified cross-talk between basal RelA activity and the IRF1-mediated interferon pathway, resulting in CDK4 down-regulation and suppression of cell-cycle progression; differential expression was assessed using LIMMA implemented in MEV, and the source data are available through GEO accession GSE65040.", "kind": "qualitative", "target": null, "evidence": [{"asset": "source:pmid:26981373", "locator": "sections[0] \"Abstract\" paragraph 1", "quote": "Analysis of the data identified cross-talk between basal RelA activity and the Interferon pathway mediated by IRF1, a target of RelA [5]."}, {"asset": "source:pmid:26981373", "locator": "sections[0] \"Abstract\" paragraph 1", "quote": "Activation of the Interferon pathway lead to down-regulation of CDK4 expression resulting in RB1 hypo-phosphorylation and suppression of cell cycle progression."}, {"asset": "source:pmid:26981373", "locator": "sections[0] \"Abstract\" paragraph 1", "quote": "The expression data was submitted to Gene Expression Ominibus (GEO) and the accession number is GSE65040."}, {"asset": "source:pmid:26981373", "locator": "sections[6] \"Gene expression analysis\" paragraph 2", "quote": "Differentially expressed genes between pairs of samples were identified using LIMMA implemented in MEV [10]."}, {"asset": "source:pmid:26981373", "locator": "sections[2] \"Direct link to gene expression data deposited in Gene Expression Omnibus (GEO)\" paragraph 2", "quote": "http://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE65040."}], "state": "complete"}], "gaps": []}, "experiment": {"state": "complete", "objective": "Genome-wide gene-expression analysis identified cross-talk between basal RelA activity and the IRF1-mediated interferon pathway, resulting in CDK4 down-regulation and suppression of cell-cycle progression; differential expression was assessed using LIMMA implemented in MEV, and the source data are available through GEO accession GSE65040.", "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:26981373"], "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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