{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,7]],"date-time":"2026-08-07T15:23:33Z","timestamp":1786116213370,"version":"build-2736575974"},"reference-count":37,"publisher":"MDPI AG","issue":"15","license":[{"start":{"date-parts":[[2026,8,6]],"date-time":"2026-08-06T00:00:00Z","timestamp":1785974400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100003995","name":"Anhui Provincial Natural Science Foundation","doi-asserted-by":"publisher","award":["2408085QH244"],"award-info":[{"award-number":["2408085QH244"]}],"id":[{"id":"10.13039\/501100003995","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cancers"],"abstract":"<jats:p>Triple-negative breast cancer (TNBC) is an aggressive subtype lacking effective targeted therapies. The molecular drivers of its progression and metabolic reprogramming remain unclear. Here, we identify cell division cycle-associated 4 (CDCA4) as a novel oncogenic driver in TNBC. Analysis of the TCGA-BRCA dataset, including 1085 breast cancer tissues and 112 normal tissues, showed that CDCA4 expression was significantly upregulated in breast cancer tissues. Subgroup analysis of TCGA-BRCA samples further showed higher CDCA4 expression (fold change = 1.707) in TNBC than in non-TNBC samples [TNBC, n = 116; non-TNBC, n = 984]. Survival analysis demonstrated that high CDCA4 expression was associated with poorer overall survival, with a hazard ratio of 1.54 (log-rank p = 0.0053). Functional assays demonstrated that CDCA4 knockdown suppresses proliferation, migration, invasion, and tumor growth in vitro and in vivo, whereas overexpression exerts opposite effects. RNA-sequencing revealed that CDCA4-regulated genes are enriched in lipid metabolism and mTOR signaling pathways. Mechanistically, CDCA4 depletion reduces intracellular lipids and the expression of lipogenic enzymes (FASN, ACC1). We show that CDCA4 activates mTOR and increases the nuclear active form of SREBP1, enhancing its promoter occupancy. Pharmacological mTOR inhibition reverses CDCA4-induced malignancy and metabolic alterations. Furthermore, Our findings suggest that SESN2 may contribute to CDCA4-mediated activation of mTOR signalling. SESN2 knockdown attenuates mTOR signaling and negates the pro-tumorigenic effects of CDCA4 overexpression. Collectively, these findings demonstrate that CDCA4 drives TNBC progression and lipid reprogramming via the SESN2\/mTOR\/SREBP1 axis, positioning CDCA4 as a potential prognostic biomarker and therapeutic target.<\/jats:p>","DOI":"10.3390\/cancers18152517","type":"journal-article","created":{"date-parts":[[2026,8,6]],"date-time":"2026-08-06T08:08:02Z","timestamp":1786003682000},"page":"2517","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["CDCA4 Promotes Lipid Metabolism in Triple-Negative Breast Cancer Through Activation of the SESN2\/mTOR\/SREBP1 Pathway"],"prefix":"10.3390","volume":"18","author":[{"given":"Jia","family":"Qi","sequence":"first","affiliation":[{"name":"Department of Breast and Thyroid Surgery, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou 510700, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ming","family":"Cai","sequence":"additional","affiliation":[{"name":"Division of Life Sciences and Medicine, Department of General Surgery, The First Affiliated Hospital of USTC, University of Science and Technology of China, Hefei 230001, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaowen","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Breast and Thyroid Surgery, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou 510700, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peng","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Breast and Thyroid Surgery, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou 510700, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiani","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Breast and Thyroid Surgery, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou 510700, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiezhong","family":"Wu","sequence":"additional","affiliation":[{"name":"Department of Breast and Thyroid Surgery, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou 510700, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Weiling","family":"Huang","sequence":"additional","affiliation":[{"name":"Department of Breast and Thyroid Surgery, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou 510700, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wenxuan","family":"Wu","sequence":"additional","affiliation":[{"name":"Division of Life Sciences and Medicine, Department of General Surgery, The First Affiliated Hospital of USTC, University of Science and Technology of China, Hefei 230001, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kunpeng","family":"Hu","sequence":"additional","affiliation":[{"name":"Department of Breast and Thyroid Surgery, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou 510700, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaoyuan","family":"Liang","sequence":"additional","affiliation":[{"name":"Department of Breast Surgery, Aviation General Hospital, Beijing 100012, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,8,6]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"61","DOI":"10.1038\/nature11412","article-title":"Comprehensive molecular portraits of human breast tumours","volume":"490","year":"2012","journal-title":"Nature"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"265","DOI":"10.1186\/s13046-022-02476-1","article-title":"Heterogeneity of triple negative breast cancer: Current advances in subtyping and treatment implications","volume":"41","author":"Asleh","year":"2022","journal-title":"J. Exp. Clin. Cancer Res."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"236","DOI":"10.1007\/s12032-024-02456-9","article-title":"The treatment landscape of triple-negative breast cancer","volume":"41","author":"Hu","year":"2024","journal-title":"Med. Oncol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"121","DOI":"10.1038\/s41523-022-00486-y","article-title":"Immunotherapy in triple negative breast cancer: Beyond checkpoint inhibitors","volume":"8","author":"Abdou","year":"2022","journal-title":"npj Breast Cancer"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"163","DOI":"10.1016\/j.clbc.2024.01.008","article-title":"Antibody-Drug Conjugates in Triple Negative Breast Cancer","volume":"24","author":"Keskinkilic","year":"2024","journal-title":"Clin. Breast Cancer"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"9083055","DOI":"10.1155\/2024\/9083055","article-title":"Targeted Treatment of Metastatic Triple-Negative Breast Cancer: A Systematic Review","volume":"2024","author":"Nielsen","year":"2024","journal-title":"Breast J."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"35633","DOI":"10.1074\/jbc.M603800200","article-title":"CDCA4 is an E2F transcription factor family-induced nuclear factor that regulates E2F-dependent transcriptional activation and cell proliferation","volume":"281","author":"Hayashi","year":"2006","journal-title":"J. Biol. Chem."},{"key":"ref_8","first-page":"1507","article-title":"CDCA4, a downstream gene of the Nrf2 signaling pathway, regulates cell proliferation and apoptosis in the MCF-7\/ADM human breast cancer cell line","volume":"17","author":"Xu","year":"2018","journal-title":"Mol. Med. Rep."},{"key":"ref_9","first-page":"4393","article-title":"Knockdown of cell division cycle-associated protein 4 expression inhibits proliferation of triple negative breast cancer MDA-MB-231 cells in vitro and in vivo","volume":"17","author":"Pang","year":"2019","journal-title":"Oncol. Lett."},{"key":"ref_10","doi-asserted-by":"crossref","unstructured":"Fang, H., Sheng, S., Chen, B., Wang, J., Mao, D., Han, Y., Liu, Y., Wang, X., Gui, S., and Zhang, T. (2022). A Pan-Cancer Analysis of the Oncogenic Role of Cell Division Cycle-Associated Protein 4 (CDCA4) in Human Tumors. Front. Immunol., 13.","DOI":"10.3389\/fimmu.2022.826337"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"724","DOI":"10.1111\/1759-7714.14800","article-title":"CDCA4 interacts with IGF2BP1 to regulate lung adenocarcinoma proliferation via the PI3K\/AKT pathway","volume":"14","author":"Feng","year":"2023","journal-title":"Thorac. Cancer"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"e38028","DOI":"10.1097\/MD.0000000000038028","article-title":"Exploring the role of CDCA4 in liver hepatocellular carcinoma using bioinformatics analysis and experiments","volume":"103","author":"Liang","year":"2024","journal-title":"Medicine"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1615\/JEnvironPatholToxicolOncol.2021039794","article-title":"STAT1 Mediates the Transcription of CircIFI30 and Promotes the Progression of Triple-Negative Breast Cancer by Up-Regulating CDCA4","volume":"41","author":"Zhang","year":"2022","journal-title":"J. Environ. Pathol. Toxicol. Oncol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"763","DOI":"10.1038\/nrc2222","article-title":"Fatty acid synthase and the lipogenic phenotype in cancer pathogenesis","volume":"7","author":"Menendez","year":"2007","journal-title":"Nat. Rev. Cancer"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"895","DOI":"10.1016\/j.metabol.2014.04.003","article-title":"De novo lipogenesis in health and disease","volume":"63","author":"Ameer","year":"2014","journal-title":"Metabolism"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"161","DOI":"10.1186\/s12964-023-01178-1","article-title":"The impact of lipid metabolism on breast cancer: A review about its role in tumorigenesis and immune escape","volume":"21","author":"Pimenta","year":"2023","journal-title":"Cell Commun. Signal"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"101376","DOI":"10.1016\/j.gendis.2024.101376","article-title":"Lipid metabolism involved in progression and drug resistance of breast cancer","volume":"12","author":"Fu","year":"2025","journal-title":"Genes Dis."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"2409","DOI":"10.3892\/ol.2016.4988","article-title":"SREBP-1 is an independent prognostic marker and promotes invasion and migration in breast cancer","volume":"12","author":"Bao","year":"2016","journal-title":"Oncol. Lett."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"216512","DOI":"10.1016\/j.canlet.2023.216512","article-title":"The lipid metabolism remodeling: A hurdle in breast cancer therapy","volume":"582","author":"Xiao","year":"2024","journal-title":"Cancer Lett."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"744","DOI":"10.1038\/s41568-018-0074-8","article-title":"mTOR signalling and cellular metabolism are mutual determinants in cancer","volume":"18","author":"Mossmann","year":"2018","journal-title":"Nat. Rev. Cancer"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"102861","DOI":"10.1016\/j.ctrv.2024.102861","article-title":"PI3K\/AKT\/mTOR inhibitors for hormone receptor-positive advanced breast cancer","volume":"132","author":"Hao","year":"2025","journal-title":"Cancer Treat. Rev."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"229","DOI":"10.1080\/13880209.2025.2488135","article-title":"Total flavonoids of litchi seed inhibit breast cancer metastasis by regulating the PI3K\/AKT\/mTOR and MAPKs signaling pathways","volume":"63","author":"Yang","year":"2025","journal-title":"Pharm. Biol."},{"key":"ref_23","doi-asserted-by":"crossref","unstructured":"Zhao, Q., Lin, X., and Wang, G. (2022). Targeting SREBP-1-Mediated Lipogenesis as Potential Strategies for Cancer. Front. Oncol., 12.","DOI":"10.3389\/fonc.2022.952371"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"3281","DOI":"10.1073\/pnas.1000323107","article-title":"mTORC1 activates SREBP-1c and uncouples lipogenesis from gluconeogenesis","volume":"107","author":"Laplante","year":"2010","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"408","DOI":"10.1016\/j.cell.2011.06.034","article-title":"mTOR complex 1 regulates lipin 1 localization to control the SREBP pathway","volume":"146","author":"Peterson","year":"2011","journal-title":"Cell"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"4205","DOI":"10.1038\/s41467-020-18020-8","article-title":"GLUT1 inhibition blocks growth of RB1-positive triple negative breast cancer","volume":"11","author":"Wu","year":"2020","journal-title":"Nat. Commun."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"1241","DOI":"10.1038\/s41467-025-56458-w","article-title":"Copy number amplification of FLAD1 promotes the progression of triple-negative breast cancer through lipid metabolism","volume":"16","author":"Song","year":"2025","journal-title":"Nat. Commun."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"3113","DOI":"10.7150\/ijbs.89942","article-title":"The PI3K\/Akt Pathway and Glucose Metabolism: A Dangerous Liaison in Cancer","volume":"20","author":"Fontana","year":"2024","journal-title":"Int. J. Biol. Sci."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"107806","DOI":"10.1016\/j.celrep.2020.107806","article-title":"mTOR Signaling and SREBP Activity Increase FADS2 Expression and Can Activate Sapienate Biosynthesis","volume":"31","author":"Triki","year":"2020","journal-title":"Cell Rep."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"28","DOI":"10.1186\/s10020-023-00763-x","article-title":"G protein-coupled estrogen receptor activates PI3K\/AKT\/mTOR signaling to suppress ferroptosis via SREBP1\/SCD1-mediated lipogenesis","volume":"30","author":"Chen","year":"2024","journal-title":"Mol. Med."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"9502","DOI":"10.1038\/srep09502","article-title":"Sestrin2 inhibits mTORC1 through modulation of GATOR complexes","volume":"5","author":"Kim","year":"2015","journal-title":"Sci. Rep."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"43","DOI":"10.1126\/science.aab2674","article-title":"Sestrin2 is a leucine sensor for the mTORC1 pathway","volume":"351","author":"Wolfson","year":"2016","journal-title":"Science"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"29","DOI":"10.1186\/s40364-022-00380-6","article-title":"Sestrin2 in cancer: A foe or a friend?","volume":"10","author":"Ala","year":"2022","journal-title":"Biomark. Res."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"611","DOI":"10.1038\/cdd.2012.157","article-title":"Sestrin2 integrates Akt and mTOR signaling to protect cells against energetic stress-induced death","volume":"20","author":"Dirat","year":"2013","journal-title":"Cell Death Differ."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"1769","DOI":"10.1074\/jbc.RA119.010857","article-title":"The GATOR2-mTORC2 axis mediates Sestrin2-induced AKT Ser\/Thr kinase activation","volume":"295","author":"Kowalsky","year":"2020","journal-title":"J. Biol. Chem."},{"key":"ref_36","doi-asserted-by":"crossref","unstructured":"Shin, J., Bae, J., Park, S., Kang, H.G., Shin, S.M., Won, G., Kim, J.S., Cho, S.G., Choi, Y., and Oh, S.M. (2020). mTOR-Dependent Role of Sestrin2 in Regulating Tumor Progression of Human Endometrial Cancer. Cancers, 12.","DOI":"10.3390\/cancers12092515"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"4215","DOI":"10.7150\/ijbs.109799","article-title":"SESN2 inhibits tubular exosome secretion and diabetic kidney disease progression by restoring the autophagy\u2013lysosome pathway","volume":"21","author":"Zheng","year":"2025","journal-title":"Int. J. Biol. Sci."}],"container-title":["Cancers"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2072-6694\/18\/15\/2517\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,8,6]],"date-time":"2026-08-06T08:21:08Z","timestamp":1786004468000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2072-6694\/18\/15\/2517"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,8,6]]},"references-count":37,"journal-issue":{"issue":"15","published-online":{"date-parts":[[2026,8]]}},"alternative-id":["cancers18152517"],"URL":"https:\/\/doi.org\/10.3390\/cancers18152517","relation":{},"ISSN":["2072-6694"],"issn-type":[{"value":"2072-6694","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,8,6]]}}}