Identification of Seven Cell Cycle-Related Genes with Unfavorable Prognosis and Construction of their TF-miRNA-mRNA regulatory network in Breast Cancer.

{"sci_version": "1.2", "schema": "https://corpus.bntrg.co.uk/sci/1.0/sci.schema.json", "id": "pmid:33403032", "kind": "science-record", "revision": 9, "content_hash": "sha256:6aa4ac745dc8be6c074b8bbaffd0c3ffe47dd6987dee37f7a8ad9f6d34c0c9cf", "created_at": "2026-11-01T15:41:21Z", "updated_at": "2026-11-01T22:45:55Z", "generator": {"name": "corpus-assay-engine", "run_id": "reading-sci-2026-11-01"}, "paper": {"state": "complete", "title": "Identification of Seven Cell Cycle-Related Genes with Unfavorable Prognosis and Construction of their TF-miRNA-mRNA regulatory network in Breast Cancer.", "doi": "10.7150/jca.48245", "pmid": "33403032", "authors": ["Zhipeng Hong", "Qinglan Wang", "Chengye Hong", "Meimei Liu", "Pengqin Qiu", "Rongrong Lin", "Xiaolan Lin", "Fangfang Chen", "Qiuhuang Li", "Lingling Liu", "Chuan Wang", "Debo Chen"], "journal": "Journal of Cancer", "year": 2021, "abstract": "Breast cancer (BC), with complex tumorigenesis and progression, remains the most common malignancy in women. We aimed to explore some novel and significant genes with unfavorable prognoses and potential pathways involved in BC initiation and progression via bioinformatics methods. BC tissue-specific microarray datasets of GSE42568, GSE45827 and GSE54002, which included a total of 651 BC tissues and 44 normal breast tissues, were obtained from the Gene Expression Omnibus (GEO) database, and 124 differentially expressed genes (DEGs) were identified between BC tissues and normal breast tissues via R software and an online Venn diagram tool. Database for Annotation, Visualization and Integration Discovery (DAVID) software showed that 65 upregulated DEGs were mainly enriched in the regulation of the cell cycle, and Search Tool for the Retrieval of Interacting Genes (STRING) software identified the 39 closest associated upregulated DEGs in protein-protein interactions (PPIs), which validated the high expression of genes in BC tissues by the Gene Expression Profiling Interactive Analysis (GEPIA) tool. In addition, 36 out of 39 BC patients showed significantly worse outcomes by Kaplan-Meier plotter (KM plotter), and an additional Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis revealed that seven genes (cyclin E2 (CCNE2), cyclin B1 (CCNB1), cyclin B2 (CCNB2), mitotic checkpoint serine/threonine kinase B (BUB1B), dual-specificity protein kinase (TTK), cell division cycle 20 (CDC20), and pituitary tumor transforming gene 1 (PTTG1)) were markedly enriched in the cell cycle pathway. Analysis of the clinicopathological characteristics of hub genes revealed that seven cell cycle-related genes (CCRGs) were significantly highly expressed in four BC subtypes (luminal A, luminal B, HER2-positive and triple-negative (TNBC)), and except for the CCNE2 gene, high expression levels were significantly associated with tumor pathological grade and stage and metastatic events of BC. Furthermore, genetic mutation analysis indicated that genetic alterations of CCRGs could also significantly affect BC patients' prognosis. A quantitative real-time polymerase chain reaction (qRT-PCR) assay found that the seven CCRGs were significantly differentially expressed in BC cell lines. Integration of published multilevel expression data and a bioinformatics computational approach were used to predict and construct a regulation mechanism: a transcription factor (TF)-microRNA (miRNA)-messenger RNA (mRNA) regulation network. The present work is the first to construct a regulatory network of TF-miRNA-mRNA in BC for CCRGs and provides new insights into the molecular mechanism of BC.", "claims": [{"id": "claim-method", "statement": "We detected and removed batch effects in each dataset (Supplementary Figure S1) and then classified the BC specimens and normal breast specimens in three microarray datasets using R software (version 3.4.4) packages edgeR and limma to identify DEGs.", "kind": "methodological", "target": null, "evidence": [{"asset": "source:pmid:33403032", "locator": "sections[4] \"Data processing and differential analysis\" paragraph 2", "quote": "We detected and removed batch effects in each dataset (Supplementary Figure S1) and then classified the BC specimens and normal breast specimens in three microarray datasets using R software (version 3.4.4) packages edgeR and limma to identify DEGs."}], "state": "complete"}, {"id": "claim-data-access", "statement": "Microarray datasets of GSE42568, GSE45827 and GSE54002 were all processed on the GPL570 platform ([HG-U133_Plus_2] Affymetrix Human Genome U133 Plus 2.0 Array) and contained 104 BC tissues and 17 normal breast tissues, 130 BC tissues and 11 normal breast tissues, and 417 BC tissues and 16 breast tissues, respectively.", "kind": "methodological", "target": null, "evidence": [{"asset": "source:pmid:33403032", "locator": "sections[3] \"Collection of microarray data information from GEO datasets\" paragraph 2", "quote": "Microarray datasets of GSE42568, GSE45827 and GSE54002 were all processed on the GPL570 platform ([HG-U133_Plus_2] Affymetrix Human Genome U133 Plus 2.0 Array) and contained 104 BC tissues and 17 normal breast tissues, 130 BC tissues and 11 normal breast tissues, and 417 BC tissues and 16 breast tissues, respectively."}], "state": "complete"}], "gaps": []}, "experiment": {"state": "complete", "objective": null, "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:33403032"], "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. This lane did not download the dataset or read its licence.", "duration_hours": null, "parameters": {}, "inputs": ["data:geo:GSE42568"], "outputs": ["the source data with its repository provenance"], "instruments": [], "reagents": []}, {"id": "run_analysis", "order": 3, "name": "Run the published analysis", "kind": "analysis", "state": "complete", "blocked_on": null, "description": "Apply the paper's statistical method to the resolved series and compare the result with the published target.", "duration_hours": null, "parameters": {}, "inputs": ["data:geo:GSE42568"], "outputs": ["the replicated result and its comparison"], "instruments": [], "reagents": []}], "materials": [], "instruments": [], "reagents": [], "conditions": {}, "gaps": []}, "data": {"state": "partial", "assets": [{"id": "source:pmid:33403032", "role": "manuscript", "format": "xml", "media_type": "application/xml", "uri": "https://doi.org/10.7150/jca.48245", "sha256": 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BC tissue-specific microarray datasets of GSE42568, GSE45827 and GSE54002,", "ecimens and normal breast specimens in three microarray datasets using R software (version 3.4.4) pa"], "order_basis": "paper_text_order:409", "id": "assay:1"}, {"role": "data_generation", "definition_id": "rna_seq", "definition_version": "99e1195c7d6f", "definition_digest": null, "required_operations": [], "support_state": "partial", "source_hashes": {"assay_lexicon": "99e1195c7d6f"}, "confidence": 0.93, "evidence": ["(KM plotter) system contained gene ChIP and RNA-seq data sources from the TCGA, European Genome-"], "order_basis": "paper_text_order:3625", "id": "assay:2"}, {"role": "data_generation", "definition_id": "cell_culture", "definition_version": "99e1195c7d6f", "definition_digest": null, "required_operations": [], "support_state": "partial", "source_hashes": {"assay_lexicon": "99e1195c7d6f"}, "confidence": 0.99, "evidence": ["mycin. MCF-7 cells and MDA-MB-231 cells were cultured in DMEM (Gibco, Carlsbad, CA, United States) co", "ithelial cell line MCF-10A and BC cell lines MCF-7 and MDA-MB-231 were purchased from the Cell", "e and 1 unit (U)/ml penicillin/streptomycin. MCF-7 cells and MDA-MB-231 cells were cultured in"], "order_basis": "paper_text_order:4149", "id": "assay:3"}, {"role": "data_generation", "definition_id": "ihc", "definition_version": "99e1195c7d6f", "definition_digest": null, "required_operations": [], "support_state": "partial", "source_hashes": {"assay_lexicon": "99e1195c7d6f"}, "confidence": 0.99, "evidence": ["e protein expression of CCRGs in BC, we used IHC to compare the protein expression between no", "es via the Human Protein Atlas database. The IHC map of CCRGs is shown in Figure 7 and confir", "f data available in the Human Protein Atlas. 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