{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,13]],"date-time":"2026-07-13T08:09:10Z","timestamp":1783930150792,"version":"3.55.0"},"reference-count":33,"publisher":"MDPI AG","issue":"14","license":[{"start":{"date-parts":[[2026,7,9]],"date-time":"2026-07-09T00:00:00Z","timestamp":1783555200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>Triple-negative breast cancer (TNBC) is characterized by a lack of estrogen, progesterone, and HER2 receptors; an aggressive phenotype; high rates of early relapse and metastasis; and the worst mortality rates among all breast cancer subtypes. Currently, there is no effective curative targeted therapy for TNBC and chemotherapy remains the primary treatment for TNBC. Therefore, there is a critical need to develop highly effective, novel therapies to improve patient survival. We previously validated FOXM1, a proto-oncogenic transcription factor, for the first time as a potential molecular target in TNBC through genetic knockdown studies in mice. We show that FOXM1 expression is associated with shorter patient survival and is a marker of poor prognosis. There is no FDA-approved FOXM1 inhibitor. We found that patients with TP53 mutations have dramatically higher FOXM1 expression, indicating that widespread TP53 mutations detected in about 80% of TNBC patients are the major driver of FOXM1 overexpression in TNBC patients. We identified its binding ability using an in silico study, and found it to be a well-known FOXM1 inhibitor that suppresses TNBC cell proliferation, migration, and invasion, and induces apoptosis. In vivo studies in mice bearing TNBC tumors demonstrated that treatment with a novel FOXM1 inhibitor incorporated in single-lipid nanoparticles suppressed the growth of TNBC tumor xenografts. In conclusion, our findings suggest that the novel FOXM1 inhibitor represents a potent and safe therapeutic strategy with significant potential for the treatment of other FOXM1-driven cancers including TNBC that currently have limited treatment options.<\/jats:p>","DOI":"10.3390\/cells15141237","type":"journal-article","created":{"date-parts":[[2026,7,9]],"date-time":"2026-07-09T08:50:56Z","timestamp":1783587056000},"page":"1237","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Targeting p53-Driven FOXM1 Suppresses Tumor Growth and Synergistically Sensitizes to Chemotherapy in Triple-Negative Breast Cancer Models"],"prefix":"10.3390","volume":"15","author":[{"given":"Sayra","family":"Dilmac","sequence":"first","affiliation":[{"name":"Department of Nanomedicine, Houston Methodist Research Institute, Houston, TX 77030, USA"},{"name":"Stephenson School of Biomedical Engineering, The University of Oklahoma, Norman, OK 73019, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nermin","family":"Kahraman","sequence":"additional","affiliation":[{"name":"Department of Nanomedicine, Houston Methodist Research Institute, Houston, TX 77030, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4037-1979","authenticated-orcid":false,"given":"Ferah Comert","family":"Onder","sequence":"additional","affiliation":[{"name":"Department of Medical Biology, Faculty of Medicine, \u00c7anakkale Onsekiz Mart University, \u00c7anakkale 17100, T\u00fcrkiye"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ogun Ali","family":"Gul","sequence":"additional","affiliation":[{"name":"Department of Nanomedicine, Houston Methodist Research Institute, Houston, TX 77030, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bulent","family":"Ozpolat","sequence":"additional","affiliation":[{"name":"Department of Nanomedicine, Houston Methodist Research Institute, Houston, TX 77030, USA"},{"name":"Department of Experimental Therapeutics, MD Anderson Cancer Center, The University of Texas, Houston, TX 77054, USA"},{"name":"Stephenson School of Biomedical Engineering, The University of Oklahoma, Norman, OK 73019, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,7,9]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1483","DOI":"10.1007\/s13346-018-0551-3","article-title":"Metastatic and triple-negative breast cancer: Challenges and treatment options","volume":"8","author":"Sapiezynski","year":"2018","journal-title":"Drug Deliv. Transl. Res."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"607","DOI":"10.1007\/s00262-020-02736-z","article-title":"Pembrolizumab and atezolizumab in triple-negative breast cancer","volume":"70","author":"Kwapisz","year":"2021","journal-title":"Cancer Immunol. Immunother."},{"key":"ref_3","doi-asserted-by":"crossref","unstructured":"Obidiro, O., Battogtokh, G., and Akala, E.O. (2023). Triple Negative Breast Cancer Treatment Options and Limitations: Future Outlook. Pharmaceutics, 15.","DOI":"10.20944\/preprints202306.0074.v1"},{"key":"ref_4","doi-asserted-by":"crossref","unstructured":"Vagia, E., Mahalingam, D., and Cristofanilli, M. (2020). The Landscape of Targeted Therapies in TNBC. Cancers, 12.","DOI":"10.3390\/cancers12040916"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"376","DOI":"10.4048\/jbc.2014.17.4.376","article-title":"Association between Pathological Complete Response and Outcome Following Neoadjuvant Chemotherapy in Locally Advanced Breast Cancer Patients","volume":"17","author":"Luangdilok","year":"2014","journal-title":"J. Breast Cancer"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1529","DOI":"10.1056\/NEJMoa2028485","article-title":"Sacituzumab Govitecan in Metastatic Triple-Negative Breast Cancer","volume":"384","author":"Bardia","year":"2021","journal-title":"N. Engl. J. Med."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"994","DOI":"10.1016\/j.annonc.2021.05.801","article-title":"Primary results from IMpassion131, a double-blind, placebo-controlled, randomised phase III trial of first-line paclitaxel with or without atezolizumab for unresectable locally advanced\/metastatic triple-negative breast cancer","volume":"32","author":"Miles","year":"2021","journal-title":"Ann. Oncol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"229","DOI":"10.1080\/14737140.2022.2023011","article-title":"Atezolizumab and pembrolizumab in triple-negative breast cancer: A meta-analysis","volume":"22","author":"Latif","year":"2022","journal-title":"Expert Rev. Anticancer Ther."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1227","DOI":"10.1002\/ijc.27767","article-title":"Distinct tumor protein p53 mutants in breast cancer subgroups","volume":"132","author":"Dumay","year":"2013","journal-title":"Int. J. Cancer"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"16619","DOI":"10.18632\/oncotarget.7672","article-title":"FOXM1 regulates expression of eukaryotic elongation factor 2 kinase and promotes proliferation, invasion and tumorgenesis of human triple negative breast cancer cells","volume":"7","author":"Hamurcu","year":"2016","journal-title":"Oncotarget"},{"key":"ref_11","doi-asserted-by":"crossref","unstructured":"Lee, Y., Kim, K.H., Kim, D.G., Cho, H.J., Kim, Y., Rheey, J., Shin, K., Seo, Y.J., Choi, Y.S., and Lee, J.I. (2015). FoxM1 Promotes Stemness and Radio-Resistance of Glioblastoma by Regulating the Master Stem Cell Regulator Sox2. PLoS ONE, 10.","DOI":"10.1371\/journal.pone.0137703"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"4708","DOI":"10.1038\/onc.2016.14","article-title":"HGF\/Met and FOXM1 form a positive feedback loop and render pancreatic cancer cells resistance to Met inhibition and aggressive phenotypes","volume":"35","author":"Cui","year":"2016","journal-title":"Oncogene"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1269","DOI":"10.21037\/jtd.2016.04.13","article-title":"Prognostic significance of FoxM1 expression in non-small cell lung cancer","volume":"8","author":"Sun","year":"2016","journal-title":"J. Thorac. Dis."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"57","DOI":"10.1186\/s12964-018-0266-6","article-title":"Regulation of the master regulator FOXM1 in cancer","volume":"16","author":"Liao","year":"2018","journal-title":"Cell Commun. Signal."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"245","DOI":"10.1158\/1535-7163.MCT-12-0712","article-title":"FOX(M1) news\u2014It is cancer","volume":"12","author":"Halasi","year":"2013","journal-title":"Mol. Cancer Ther."},{"key":"ref_16","doi-asserted-by":"crossref","unstructured":"Dilmac, S., Hamurcu, Z., and Ozpolat, B. (2024). Therapeutic Landscape of FOXM1 in Triple-Negative Breast Cancer and Aggressive Solid Cancers. Cancers, 16.","DOI":"10.3390\/cancers16223823"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"23","DOI":"10.7314\/APJCP.2015.16.1.23","article-title":"FoxM1 as a novel therapeutic target for cancer drug therapy","volume":"16","author":"Xu","year":"2015","journal-title":"Asian Pac. J. Cancer Prev."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"485","DOI":"10.1007\/s10549-017-4207-7","article-title":"FOXM1 transcriptionally regulates expression of integrin beta1 in triple-negative breast cancer","volume":"163","author":"Hamurcu","year":"2017","journal-title":"Breast Cancer Res. Treat."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"e70296","DOI":"10.1002\/ddr.70296","article-title":"Design, Synthesis, Biological Evaluation, and Molecular Modeling Studies of Novel 2-Aminothiazole Derivatives as Potential FOXM1 Inhibitors for Triple-Negative Breast Cancer Therapy and Structure-Activity Relationship","volume":"87","author":"Abusharkh","year":"2026","journal-title":"Drug Dev. Res."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"e2400504","DOI":"10.1002\/ardp.202400504","article-title":"Novel benzothiazole\/benzothiazole thiazolidine-2,4-dione derivatives as potential FOXM1 inhibitors: In silico, synthesis, and in vitro studies","volume":"357","author":"Abusharkh","year":"2024","journal-title":"Arch. Pharm."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"188","DOI":"10.1007\/s12032-024-02427-0","article-title":"A drug repurposing study identifies novel FOXM1 inhibitors with in vitro activity against breast cancer cells","volume":"41","author":"Abusharkh","year":"2024","journal-title":"Med. Oncol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"12","DOI":"10.1186\/s13062-020-00267-2","article-title":"AMDock: A versatile graphical tool for assisting molecular docking with Autodock Vina and Autodock4","volume":"15","author":"Valiente","year":"2020","journal-title":"Biol. Direct"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"84","DOI":"10.1038\/s41419-017-0156-7","article-title":"Honokiol is a FOXM1 antagonist","volume":"9","author":"Halasi","year":"2018","journal-title":"Cell Death Dis."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"197","DOI":"10.1016\/j.jmgm.2018.01.009","article-title":"Untying the knot of transcription factor druggability: Molecular modeling study of FOXM1 inhibitors","volume":"80","author":"Dominguez","year":"2018","journal-title":"J. Mol. Graph. Model."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"103269","DOI":"10.1016\/j.bioorg.2019.103269","article-title":"A structure-activity relationship study of Forkhead Domain Inhibitors (FDI): The importance of halogen binding interactions","volume":"93","author":"Dakhili","year":"2019","journal-title":"Bioorg. Chem."},{"key":"ref_26","first-page":"77","article-title":"Silencing of FoxM1 blocks growth, migration and invasion of papillary thyroid carcinoma cells","volume":"19","author":"Wang","year":"2020","journal-title":"Oncol. Lett."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"91","DOI":"10.1038\/s41571-021-00565-2","article-title":"Treatment landscape of triple-negative breast cancer\u2014Expanded options, evolving needs","volume":"19","author":"Bianchini","year":"2022","journal-title":"Nat. Rev. Clin. Oncol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"5165","DOI":"10.1038\/ncomms6165","article-title":"Suppression of the FOXM1 transcriptional programme via novel small molecule inhibition","volume":"5","author":"Gormally","year":"2014","journal-title":"Nat. Commun."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"725","DOI":"10.1038\/nchem.1114","article-title":"The transcription factor FOXM1 is a cellular target of the natural product thiostrepton","volume":"3","author":"Hegde","year":"2011","journal-title":"Nat. Chem."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"186","DOI":"10.7150\/ijbs.10634","article-title":"FOXM1 promotes lung adenocarcinoma invasion and metastasis by upregulating SNAIL","volume":"11","author":"Wei","year":"2015","journal-title":"Int. J. Biol. Sci."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"601","DOI":"10.1016\/j.ygyno.2012.08.036","article-title":"FOXM1 promotes tumor cell invasion and correlates with poor prognosis in early-stage cervical cancer","volume":"127","author":"He","year":"2012","journal-title":"Gynecol. Oncol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"104","DOI":"10.1016\/j.canlet.2013.07.004","article-title":"FOXM1 promotes the epithelial to mesenchymal transition by stimulating the transcription of Slug in human breast cancer","volume":"340","author":"Yang","year":"2013","journal-title":"Cancer Lett."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"1843","DOI":"10.1093\/carcin\/bgs167","article-title":"FOXM1 mediates Dox resistance in breast cancer by enhancing DNA repair","volume":"33","author":"Park","year":"2012","journal-title":"Carcinogenesis"}],"container-title":["Cells"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4409\/15\/14\/1237\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,7,13]],"date-time":"2026-07-13T07:33:11Z","timestamp":1783927991000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4409\/15\/14\/1237"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,7,9]]},"references-count":33,"journal-issue":{"issue":"14","published-online":{"date-parts":[[2026,7]]}},"alternative-id":["cells15141237"],"URL":"https:\/\/doi.org\/10.3390\/cells15141237","relation":{},"ISSN":["2073-4409"],"issn-type":[{"value":"2073-4409","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,7,9]]}}}