Hyperglycemia induces PFKFB3 overexpression and promotes malignant phenotype of breast cancer through RAS/MAPK activation.

{"sci_version": "1.2", "schema": "https://corpus.bntrg.co.uk/sci/1.0/sci.schema.json", "id": "pmid:36973739", "kind": "science-record", "revision": 2, "content_hash": "sha256:270a24dc952476fe5a1fbad16fcd69ce8474d7fc3a13e680910817af83682b57", "created_at": "2026-11-01T19:01:37Z", "updated_at": "2026-11-01T21:30:27Z", "generator": {"name": "corpus-assay-engine", "run_id": "reading-sci-2026-11-01"}, "paper": {"state": "complete", "title": "Hyperglycemia induces PFKFB3 overexpression and promotes malignant phenotype of breast cancer through RAS/MAPK activation.", "doi": "10.1186/s12957-023-02990-2", "pmid": "36973739", "authors": ["Xiao Cheng", "Xiupeng Jia", "Chunnian Wang", "Shangyan Zhou", "Jiayi Chen", "Lei Chen", "Jinping Chen"], "journal": "World journal of surgical oncology", "year": 2023, "abstract": "BACKGROUND: Breast cancer is the most common tumor in women worldwide. Diabetes mellitus is a global chronic metabolic disease with increasing incidence. Diabetes mellitus has been reported to positively regulate the development of many tumors. However, the specific mechanism of hyperglycemic environment regulating breast cancer remains unclear. PFKFB3 (6-phosphofructose-2-kinase/fructose-2, 6-bisphosphatase 3) is a key regulatory factor of the glycolysis process in diabetes mellitus, as well as a promoter of breast cancer. So, we want to explore the potential link between PFKFB3 and the poor prognosis of breast cancer patients with hyperglycemia in this study.\nMETHODS: Cell culture was utilized to construct different-glucose breast cancer cell lines. Immunohistochemistry was adopted to analyze the protein level of PFKFB3 in benign breast tissues, invasive ductal carcinoma with diabetes and invasive ductal carcinoma without diabetes. The Kaplan-Meier plotter database and GEO database (GSE61304) was adopted to analyze the survival of breast cancer patients with different PFKFB3 expression. Western blot was adopted to analyze the protein level of PFKFB3, epithelial-mesenchymal transition (EMT)-related protein and extracellular regulated protein kinases (ERK) in breast cancer cells. Gene Set Cancer Analysis (GSCA) was utilized to investigate the potential downstream signaling pathways of PFKFB3. TargetScan and OncomiR were utilized to explore the potential mechanism of PFKFB3 overexpression by hyperglycemia. Transfections (including siRNAs and miRNA transfection premiers) was utilized to restrain or mimic the expression of the corresponding RNA. Cell functional assays (including cell counting, MTT, colony formation, wound-healing, and cell migration assays) were utilized to explore the proliferation and migration of breast cancer cells.\nRESULTS: In this study, we demonstrated that the expression of PFKFB3 in breast cancer complicated with hyperglycemia was higher than that in breast cancer with euglycemia through cell experiment in vitro and histological experiment. PFKFB3 overexpression decreased the survival period of breast cancer patients and was correlated with a number of clinicopathological parameters of breast cancer complicated with diabetes. PFKFB3 promoted the proliferation and migration of breast cancer in a hyperglycemic environment and might be regulated by miR-26. In addition, PFKFB3 stimulated epithelial-mesenchymal transition of breast cancer in a hyperglycemic environment. In terms of downstream mechanism exploration, we predicted and verified the cancer-promoting effect of PFKFB3 in breast cancer complicated with hyperglycemia through RAS/MAPK pathway.\nCONCLUSIONS: In conclusion, PFKFB3 could be overexpressed by hyperglycemia and might be a potential therapeutic target for breast cancer complicated with diabetes.", "claims": [{"id": "claim-method", "statement": "The survival analyses were conducted with Kaplan–Meier curve.", "kind": "methodological", "target": null, "evidence": [{"asset": "source:pmid:36973739", "locator": "sections[10] \"Statistical analysis\" paragraph 2", "quote": "The survival analyses were conducted with Kaplan–Meier curve."}], "state": "complete"}, {"id": "claim-data-access", "statement": "All data related to the results of this study are available within the article.", "kind": "methodological", "target": null, "evidence": [{"asset": "source:pmid:36973739", "locator": "sections[24] \"notes\" paragraph 1", "quote": "All data related to the results of this study are available within the article."}], "state": "complete"}, {"id": "claim-target-result", "statement": "PFKFB3 overexpression decreased the survival period of breast cancer patients and was correlated with a number of clinicopathological parameters of breast cancer complicated with diabetes.", "kind": "qualitative", "target": null, "evidence": [{"asset": "source:pmid:36973739", "locator": "sections[0] \"Abstract\" paragraph 3", "quote": "PFKFB3 overexpression decreased the survival period of breast cancer patients and was correlated with a number of clinicopathological parameters of breast cancer complicated with diabetes."}], "state": "complete"}], "gaps": []}, "experiment": {"state": "complete", "objective": "PFKFB3 overexpression decreased the survival period of breast cancer patients and was correlated with a number of clinicopathological parameters of breast cancer complicated with diabetes.", "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:36973739"], "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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Immunohistochemistry was adopted to analyze the protein level of", "oma with/without diabetes were compared with IHC based on the multi-center cases we collected", "ma with or without diabetes were detected by IHC. The magnification of the photographs was 20"], "order_basis": "paper_text_order:841", "id": "assay:1"}, {"role": "data_generation", "definition_id": "western_blot", "definition_version": "99e1195c7d6f", "definition_digest": null, "required_operations": [], "support_state": "partial", "source_hashes": {"assay_lexicon": "99e1195c7d6f"}, "confidence": 0.93, "evidence": ["r patients with different PFKFB3 expression. 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Transfections (including siRNAs and miRNA transfection premiers) was utilized to restrain or mimic"], "order_basis": "paper_text_order:1651", "id": "assay:3"}, {"role": "data_generation", "definition_id": "apoptosis_assay", "definition_version": "99e1195c7d6f", "definition_digest": null, "required_operations": [], "support_state": "partial", "source_hashes": {"assay_lexicon": "99e1195c7d6f"}, "confidence": 0.93, "evidence": ["functional assays (including cell counting, MTT, colony formation, wound-healing, and cell m"], "order_basis": "paper_text_order:1799", "id": "assay:4"}, {"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": ["rent-glucose breast cancer cell lines (cells cultured with different glucose concentrations were herein", "ast cancer cell lines (BT474 and MCF-7) were cultured in 1640 mediums with different concentrations o", "ure Human breast cancer cell lines BT474 and MCF-7 were purchased from ATCC (the American Type", "ations were hereinafter referred to as BT474/MCF-7–5.5/15/25 mM (mmol/L)). 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