{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T17:55:21Z","timestamp":1785434121855,"version":"3.56.0"},"reference-count":52,"publisher":"MDPI AG","issue":"15","license":[{"start":{"date-parts":[[2026,7,28]],"date-time":"2026-07-28T00:00:00Z","timestamp":1785196800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100005888","name":"Medical University of Lodz","doi-asserted-by":"crossref","award":["503\/0\u2013078\u201302\/503\u201301\u2013001"],"award-info":[{"award-number":["503\/0\u2013078\u201302\/503\u201301\u2013001"]}],"id":[{"id":"10.13039\/501100005888","id-type":"DOI","asserted-by":"crossref"}]},{"award":["503\/0\u2013078\u201302\/503\u201301\u2013001"],"award-info":[{"award-number":["503\/0\u2013078\u201302\/503\u201301\u2013001"]}],"id":[{"id":"https:\/\/ror.org\/02t4ekc95","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Int. J. Mol. Sci.","IJMS"],"abstract":"<jats:p>WWOX and HIF1A are linked to hypoxia-driven metabolic and immune modulation in cancer. We examined whether the WWOX\/HIF1A expression ratio acts as a context-dependent molecular integrator across breast cancer (BRCA) subtypes and ovarian carcinoma (OV). We analyzsed TCGA RNA-seq and clinical data from BRCA (n = 390) and OV (n = 228), using neoplasm cancer status as a proxy for disease-free survival (DFS). Patients were stratified by subtype-specific WWOX\/HIF1A ratio cutpoints for exploratory Kaplan\u2013-Meier analyses, and the ratio was also modelled as a standardizsed continuous covariate in Cox regression. Transcriptomic, pathway, immune-cell and hormone-related profiles were examined in relation to ratio status, with all multivariable and cutpoint-based findings treated as hypothesis-generating. The WWOX\/HIF1A ratio does not act as a uniform or strongly predictive prognostic marker but instead delineates distinct biological states whose association with DFS is modest, context-dependent and statistically fragile in TCGA. Higher ratios are linked to more favourable DFS only in basal-like and HER2-enriched BRCA, together with oxidative phosphorylation, ribosomal and reduced ADAM10-linked Notch and monocyte\/macrophage signatures. In luminal A BRCA and OV, lower ratios are linked to relatively favourable DFS and coincide with cytokine\/JAK\u2013STAT signalling, cytotoxic immune signatures and coordinated metabolic\u2013endocrine programmes, whereas luminal B shows mixed immune and metabolic patterns. In this TCGA-based analysis, the WWOX\/HIF1A ratio functions as a context-dependent molecular index of hypoxia, immune and hormone-related states rather than a strong, generalisable DFS predictor. The observed subtype-specific survival trends (high-ratio favourability in basal\/HER2, low-ratio favourability in luminal A,B and OV) are non-significant and exploratory, and all ratio-based survival patterns require confirmation in independent cohorts and functional studies.<\/jats:p>","DOI":"10.3390\/ijms27156740","type":"journal-article","created":{"date-parts":[[2026,7,28]],"date-time":"2026-07-28T11:45:26Z","timestamp":1785239126000},"page":"6740","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["WWOX\/HIF1A Balance Delineates Context-Dependent Molecular States in Breast Cancer Subtypes and Ovarian Carcinoma"],"prefix":"10.3390","volume":"27","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2726-3922","authenticated-orcid":false,"given":"Raneem Y.","family":"Hammouz","sequence":"first","affiliation":[{"name":"Department of Molecular Carcinogenesis, Medical University of Lodz, \u017beligowskiego 7\/9, 90-752 Lodz, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0008-2237-2274","authenticated-orcid":false,"given":"Kinga","family":"Maciejek","sequence":"additional","affiliation":[{"name":"Department of Molecular Carcinogenesis, Medical University of Lodz, \u017beligowskiego 7\/9, 90-752 Lodz, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4570-4154","authenticated-orcid":false,"given":"Andrzej K.","family":"Bednarek","sequence":"additional","affiliation":[{"name":"Department of Molecular Carcinogenesis, Medical University of Lodz, \u017beligowskiego 7\/9, 90-752 Lodz, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,7,28]]},"reference":[{"key":"ref_1","first-page":"209","article-title":"Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries","volume":"71","author":"Sung","year":"2021","journal-title":"CA Cancer J. Clin."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1376","DOI":"10.1016\/S0140-6736(13)62146-7","article-title":"Ovarian cancer","volume":"384","author":"Jayson","year":"2014","journal-title":"Lancet"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"47","DOI":"10.1146\/annurev-pathol-012513-104720","article-title":"Oxygen Sensing, Hypoxia-Inducible Factors, and Disease Pathophysiology","volume":"9","author":"Semenza","year":"2014","journal-title":"Annu. Rev. Pathol. Mech. Dis."},{"key":"ref_4","doi-asserted-by":"crossref","unstructured":"Bary\u0142a, I., Stycze\u0144-Binkowska, E., P\u0142uciennik, E., Ko\u015bla, K., and Bednarek, A.K. (2022). The WWOX\/HIF1A Axis Downregulation Alters Glucose Metabolism and Predispose to Metabolic Disorders. Int. J. Mol. Sci., 23.","DOI":"10.3390\/ijms23063326"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"e965640","DOI":"10.4161\/23723548.2014.965640","article-title":"WWOX loss activates aerobic glycolysis","volume":"2","author":"Seewaldt","year":"2015","journal-title":"Mol. Cell. Oncol."},{"key":"ref_6","doi-asserted-by":"crossref","unstructured":"Springer, M., Burakgazi, Z.A., Domukhovska, A., Nafchi, B., Beary, M.C., Acquisto, A., Acquisto, J., Komarov, V., Jensen, M., and Gulledge, B. (2025). HIF-1\u03b1-Mediated Disruption of Cellular Junctions: The Impact of Hypoxia on the Tumor Microenvironment and Invasion. Int. J. Mol. Sci., 26.","DOI":"10.3390\/ijms26115101"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"128","DOI":"10.1038\/s41392-024-01828-x","article-title":"Notch signalling pathway in cancer: From mechanistic insights to targeted therapies","volume":"9","author":"Shi","year":"2024","journal-title":"Signal Transduct. Target. Ther."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"286","DOI":"10.1016\/j.nbd.2013.10.009","article-title":"Evidence that collaboration between HIF-1\u03b1 and Notch-1 promotes neuronal cell death in ischemic stroke","volume":"62","author":"Cheng","year":"2014","journal-title":"Neurobiol. Dis."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"315","DOI":"10.1186\/s12967-025-06282-z","article-title":"Notch signalling in the tumor immune microenvironment of colorectal cancer: Mechanisms and therapeutic opportunities","volume":"23","author":"Sun","year":"2025","journal-title":"J. Transl. Med."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"217865","DOI":"10.1016\/j.canlet.2025.217865","article-title":"The role of tumor microenvironment and immune cell crosstalk in triple-negative breast cancer (TNBC): Emerging therapeutic opportunities","volume":"628","author":"Sabit","year":"2025","journal-title":"Cancer Lett."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1805","DOI":"10.1038\/cdd.2014.95","article-title":"Tumor suppressor WWOX regulates glucose metabolism via HIF1\u03b1 modulation","volume":"21","author":"Aqeilan","year":"2014","journal-title":"Cell Death Differ."},{"key":"ref_12","doi-asserted-by":"crossref","unstructured":"Ko\u015bla, K., P\u0142uciennik, E., Stycze\u0144-Binkowska, E., Nowakowska, M., Orzechowska, M., and Bednarek, A.K. (2019). The WWOX Gene Influences Cellular Pathways in the Neuronal Differentiation of Human Neural Progenitor Cells. Front. Cell. Neurosci., 13.","DOI":"10.3389\/fncel.2019.00391"},{"key":"ref_13","doi-asserted-by":"crossref","unstructured":"Zhu, M., Iwano, T., and Takeda, S. (2019). Estrogen and EGFR Pathways Regulate Notch signalling in Opposing Directions for Multi-Ciliogenesis in the Fallopian Tube. Cells, 8.","DOI":"10.3390\/cells8080933"},{"key":"ref_14","doi-asserted-by":"crossref","unstructured":"Taouis, K., Driouch, K., Lidereau, R., and Lallemand, F. (2021). Molecular Functions of WWOX Potentially Involved in Cancer Development. Cells, 10.","DOI":"10.3390\/cells10051051"},{"key":"ref_15","doi-asserted-by":"crossref","unstructured":"Bary\u0142a, I., Hammouz, R.Y., Maciejek, K., and Bednarek, A.K. (2025). Prognostic Significance of WWOX\/HIF1A Ratio in Cancer Subtypes: Insights into Metabolism, ECM, and EMT. Biology, 14.","DOI":"10.3390\/biology14091151"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"19771","DOI":"10.1038\/srep19771","article-title":"Generation of 2,000 breast cancer metabolic landscapes reveals a poor prognosis group with active serotonin production","volume":"6","author":"Leoncikas","year":"2016","journal-title":"Sci. Rep."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"207","DOI":"10.1093\/nar\/30.1.207","article-title":"Gene Expression Omnibus: NCBI gene expression and hybridization array data repository","volume":"30","author":"Edgar","year":"2002","journal-title":"Nucleic Acids Res."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"11149","DOI":"10.1002\/cam4.5698","article-title":"Role of tumor microenvironment in cancer progression and therapeutic strategy","volume":"12","author":"Wang","year":"2023","journal-title":"Cancer Med."},{"key":"ref_19","doi-asserted-by":"crossref","unstructured":"Sureka, N., Maheshwari, R., Agravat, A., Singhal, S., Zaman, S., Rishi, B., Siraj, F., Zaheer, S., and Misra, A. (2026). Hypoxic microenvironment in cancer: Role in metabolic reprogramming. Front. Oncol., 16.","DOI":"10.3389\/fonc.2026.1771365"},{"key":"ref_20","doi-asserted-by":"crossref","unstructured":"Chakraborti, S. (2022). Cancer Stem Cell Oxidative Phosphorylation: Target for Cancer Therapy. Handbook of Oxidative Stress in Cancer: Therapeutic Aspects, Springer.","DOI":"10.1007\/978-981-16-5422-0"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"847","DOI":"10.1007\/s13402-023-00801-0","article-title":"Crosstalk between oxidative phosphorylation and immune escape in cancer: A new concept of therapeutic targets selection","volume":"46","author":"Qiu","year":"2023","journal-title":"Cell. Oncol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"156271","DOI":"10.1016\/j.prp.2025.156271","article-title":"Hypoxia-driven metabolic and molecular reprogramming: From tumor microenvironment to therapeutic interventions","volume":"276","author":"Devi","year":"2025","journal-title":"Pathol. Res. Pract."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"210","DOI":"10.1186\/s12943-025-02407-6","article-title":"Metabolic checkpoints in immune cell reprogramming: Rewiring immunometabolism for cancer therapy","volume":"24","author":"Lv","year":"2025","journal-title":"Mol. Cancer"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"417","DOI":"10.1016\/j.cels.2015.12.004","article-title":"The Molecular Signatures Database Hallmark Gene Set Collection","volume":"1","author":"Liberzon","year":"2015","journal-title":"Cell Syst."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"2025","DOI":"10.1152\/physrev.00029.2017","article-title":"Intriguing Roles for Endothelial ADAM10\/Notch signalling in the Development of Organ-Specific Vascular Beds","volume":"98","author":"Alabi","year":"2018","journal-title":"Physiol. Rev."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"2559","DOI":"10.7150\/jca.24601","article-title":"ADAM10 Sheddase Activity is a Potential Lung-Cancer Biomarker","volume":"9","author":"Yoneyama","year":"2018","journal-title":"J. Cancer"},{"key":"ref_27","doi-asserted-by":"crossref","unstructured":"Kar, R., Jha, N.K., Jha, S.K., Sharma, A., Dholpuria, S., Asthana, N., Chaurasiya, K., Singh, V.K., Burgee, S., and Nand, P. (2019). A \u201cNOTCH\u201d Deeper into the Epithelial-To-Mesenchymal Transition (EMT) Program in Breast Cancer. Genes, 10.","DOI":"10.3390\/genes10120961"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"e70338","DOI":"10.1002\/mco2.70338","article-title":"Targeting the Hippo\/YAP Pathway: A Promising Approach for Cancer Therapy and Beyond","volume":"6","author":"Bala","year":"2025","journal-title":"MedComm"},{"key":"ref_29","doi-asserted-by":"crossref","unstructured":"Cai, L., Rogers, T.J., Mousavi Jafarabad, R., Vu, H., Yang, C., Novaresi, N., Gal\u00e1n-Cobo, A., Girard, L., Ostrin, E.J., and Fahrmann, J.F. (2025). High KYNU Expression Is Associated with Poor Prognosis, KEAP1\/STK11 Mutations, and Immunosuppressive Metabolism in Patient-Derived but Not Murine Lung Adenocarcinomas. Cancers, 17.","DOI":"10.3390\/cancers17101681"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"3220","DOI":"10.1080\/15384101.2015.1084445","article-title":"Targeting CDK6 in cancer: State of the art and new insights","volume":"14","author":"Tadesse","year":"2015","journal-title":"Cell Cycle"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"245","DOI":"10.1016\/j.addr.2020.07.013","article-title":"Lipids and cancer: Emerging roles in pathogenesis, diagnosis and therapeutic intervention","volume":"159","author":"Butler","year":"2020","journal-title":"Adv. Drug Deliv. Rev."},{"key":"ref_32","doi-asserted-by":"crossref","unstructured":"Qian, X.L., Li, Y.Q., Yu, B., Gu, F., Liu, F.F., Li, W.D., Zhang, X.-M., and Fu, L. (2013). Syndecan Binding Protein (SDCBP) Is Overexpressed in Estrogen Receptor Negative Breast Cancers, and Is a Potential Promoter for Tumor Proliferation. PLoS ONE, 8.","DOI":"10.1371\/journal.pone.0060046"},{"key":"ref_33","doi-asserted-by":"crossref","unstructured":"Himes, B.E., Jiang, X., Wagner, P., Hu, R., Wang, Q., Klanderman, B., Whitaker, R.M., Duan, Q., Lasky-Su, J., and Nikolos, C. (2014). RNA-Seq Transcriptome Profiling Identifies CRISPLD2 as a Glucocorticoid Responsive Gene that Modulates Cytokine Function in Airway Smooth Muscle Cells. PLoS ONE, 9.","DOI":"10.1371\/journal.pone.0099625"},{"key":"ref_34","doi-asserted-by":"crossref","unstructured":"Xiao, Y., Fan, J., Li, Z., and Hou, Y. (2024). DDX21 at the Nexus of RNA Metabolism, Cancer Oncogenesis, and Host\u2013Virus Crosstalk: Decoding Its Biomarker Potential and Therapeutic Implications. Int. J. Mol. Sci., 25.","DOI":"10.3390\/ijms252413581"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"412","DOI":"10.5306\/wjco.v5.i3.412","article-title":"Biological subtypes of breast cancer: Prognostic and therapeutic implications","volume":"5","author":"Yersal","year":"2014","journal-title":"World J. Clin. Oncol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"57","DOI":"10.2147\/JHC.S340471","article-title":"CtBP1 Mediates Hypoxia-Induced Sarcomatoid Transformation in Hepatocellular Carcinoma","volume":"9","author":"Zhang","year":"2022","journal-title":"J. Hepatocell. Carcinoma"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"3083","DOI":"10.1038\/onc.2015.407","article-title":"CDK6\u2014A review of the past and a glimpse into the future: From cell-cycle control to transcriptional regulation","volume":"35","author":"Tigan","year":"2016","journal-title":"Oncogene"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"66","DOI":"10.1080\/19768354.2024.2321354","article-title":"Transcriptional corepressor activity of CtBP1 is regulated by ISG15 modification","volume":"28","author":"Lim","year":"2024","journal-title":"Anim. Cells Syst."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"727","DOI":"10.1158\/1541-7786.MCR-11-0604","article-title":"Basal-like breast cancer cells induce phenotypic and genomic changes in macrophages","volume":"10","author":"Stewart","year":"2012","journal-title":"Mol. Cancer Res."},{"key":"ref_40","doi-asserted-by":"crossref","unstructured":"Knutsen, E., Das Sajib, S., Fiskaa, T., Lorens, J., Gudjonsson, T., M\u00e6landsmo, G.M., Johansen, S.D., Seternes, O.-M., and Perander, M. (2023). Identification of a core EMT signature that separates basal-like breast cancers into partial- and post-EMT subtypes. Front. Oncol., 13.","DOI":"10.3389\/fonc.2023.1249895"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"107649","DOI":"10.1016\/j.phrs.2025.107649","article-title":"The role of HIF-1\u03b1 in hypoxic metabolic reprogramming in osteoarthritis","volume":"213","author":"Zhang","year":"2025","journal-title":"Pharmacol. Res."},{"key":"ref_42","doi-asserted-by":"crossref","unstructured":"Cancer Genome Atlas Research Network, Weinstein, J.N., Collisson, E.A., Mills, G.B., Shaw, K.R.M., Ozenberger, B.A., Ellrott, K., Shmulevich, I., Sander, C., and Stuart, J.M. (2013). The Cancer Genome Atlas Pan-Cancer analysis project. Nat. Genet., 45, 1113\u20131120.","DOI":"10.1038\/ng.2764"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"139","DOI":"10.1093\/bioinformatics\/btp616","article-title":"edgeR: A Bioconductor package for differential expression analysis of digital gene expression data","volume":"26","author":"Robinson","year":"2010","journal-title":"Bioinformatics"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"W212","DOI":"10.1093\/nar\/gkz446","article-title":"ChEA3: Transcription factor enrichment analysis by orthogonal omics integration","volume":"47","author":"Keenan","year":"2019","journal-title":"Nucleic Acids Res."},{"key":"ref_45","doi-asserted-by":"crossref","unstructured":"The ENCODE Project Consortium (2012). An integrated encyclopedia of DNA elements in the human genome. Nature, 489, 57\u201374.","DOI":"10.1038\/nature11247"},{"key":"ref_46","unstructured":"(2026, July 10). Alexey Sergushichev [Aut, C. fgsea [Internet]. Bioconductor. Available online: https:\/\/doi.org\/10.18129\/B9.BIOC.FGSEA."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"15545","DOI":"10.1073\/pnas.0506580102","article-title":"Gene set enrichment analysis: A knowledge-based approach for interpreting genome-wide expression profiles","volume":"102","author":"Subramanian","year":"2005","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"1","DOI":"10.18637\/jss.v033.i01","article-title":"Regularization Paths for Generalized Linear Models via Coordinate Descent","volume":"33","author":"Friedman","year":"2010","journal-title":"J. Stat. Softw."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"218","DOI":"10.1186\/s13059-016-1070-5","article-title":"Estimating the population abundance of tissue-infiltrating immune and stromal cell populations using gene expression","volume":"17","author":"Becht","year":"2016","journal-title":"Genome Biol."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"W509","DOI":"10.1093\/nar\/gkaa407","article-title":"TIMER2.0 for analysis of tumor-infiltrating immune cells","volume":"48","author":"Li","year":"2020","journal-title":"Nucleic Acids Res."},{"key":"ref_51","unstructured":"Etienne, B., and De Reyni\u00e8s, A. (R Package MCPcounter, 2016). R Package MCPcounter, version 1.1."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"1686","DOI":"10.21105\/joss.01686","article-title":"Welcome to the Tidyverse","volume":"4","author":"Wickham","year":"2019","journal-title":"J. Open Source Softw."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/27\/15\/6740\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T04:12:05Z","timestamp":1785384725000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/27\/15\/6740"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,7,28]]},"references-count":52,"journal-issue":{"issue":"15","published-online":{"date-parts":[[2026,8]]}},"alternative-id":["ijms27156740"],"URL":"https:\/\/doi.org\/10.3390\/ijms27156740","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,7,28]]}}}