{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,17]],"date-time":"2026-06-17T04:53:52Z","timestamp":1781672032047,"version":"3.54.5"},"reference-count":53,"publisher":"MDPI AG","issue":"12","license":[{"start":{"date-parts":[[2026,6,9]],"date-time":"2026-06-09T00:00:00Z","timestamp":1780963200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>The dynamic crosstalk between the tumor microenvironment (TME) and triple negative breast cancer (TNBC) cells plays a critical role in tumor progression and treatment resistance. Recent studies have highlighted the involvement of IL-20 receptor subunit alpha (IL-20RA) signaling in BC, where its overexpression modulates oncogenic pathways contributing to invasion and metastasis. Epigenetic dysregulation by Bromodomain and Extra-Terminal domain (BET) proteins critically influences key oncogenic pathways and cytokine expression in TNBC. Given that the BET-inhibitor JQ1 blocks TNBC cell growth, in this study we investigated its potential regulatory effects on the IL-20RA pathway. IL-20RA was found expressed across multiple BC cell lines compared to non-tumorigenic cells, with the highest levels detected in MDA-MB-231 and MDA-MB-468 cells. In both cell lines, JQ1 treatment significantly downregulated IL-20RA expression at gene and protein levels, accompanied by a reduction in the oncogenic JAK\/STAT signaling pathway, and programmed death-ligand 1 (PD-L1) expression. Parallel in vivo experiments using TNBC xenograft models confirmed these findings, showing reduced IL-20RA and PD-L1 expression alongside decreased phosphorylation of JAK and STAT3. Overall, this study uncovers a novel interplay between BET inhibition and the IL-20RA\/STAT3 axis, suggesting JQ1 as a valid therapeutic option for TNBC characterized by high IL-20RA expression.<\/jats:p>","DOI":"10.3390\/ijms27125233","type":"journal-article","created":{"date-parts":[[2026,6,10]],"date-time":"2026-06-10T06:33:44Z","timestamp":1781073224000},"page":"5233","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["JQ1 Downregulates IL-20RA Expression in Triple Negative Breast Cancer Cells In Vitro and In Vivo"],"prefix":"10.3390","volume":"27","author":[{"given":"Valentina","family":"Maggisano","sequence":"first","affiliation":[{"name":"Department of Health Sciences, University \u201cMagna Graecia\u201d of Catanzaro, 88100 Catanzaro, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Salvatore","family":"Panza","sequence":"additional","affiliation":[{"name":"Department of Experimental and Clinical Medicine, University \u201cMagna Graecia\u201d of Catanzaro, 88100 Catanzaro, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3603-5972","authenticated-orcid":false,"given":"Antonella","family":"Verrienti","sequence":"additional","affiliation":[{"name":"Department of Translational and Precision Medicine, Sapienza University of Rome, 00185 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1101-8874","authenticated-orcid":false,"given":"Giovanni Enrico","family":"Lombardo","sequence":"additional","affiliation":[{"name":"Department of Medicine and Surgery, University of Enna \u201cKore\u201d, 94100 Enna, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stefania","family":"Catalano","sequence":"additional","affiliation":[{"name":"Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, 87036 Arcavacata di Rende (Cosenza), Italy"},{"name":"Centro Sanitario, University of Calabria, 87036 Arcavacata di Rende (Cosenza), Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stefania","family":"Bulotta","sequence":"additional","affiliation":[{"name":"Department of Health Sciences, University \u201cMagna Graecia\u201d of Catanzaro, 88100 Catanzaro, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,6,9]]},"reference":[{"key":"ref_1","first-page":"229","article-title":"Global cancer statistics 2022: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries","volume":"74","author":"Bray","year":"2024","journal-title":"CA Cancer J. Clin."},{"key":"ref_2","first-page":"12","article-title":"Cancer statistics, 2024","volume":"74","author":"Siegel","year":"2024","journal-title":"CA A Cancer J. Clin."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"288","DOI":"10.1001\/jama.2018.19323","article-title":"Breast cancer treatment: A review","volume":"321","author":"Waks","year":"2019","journal-title":"JAMA"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"18","DOI":"10.1016\/j.cancergen.2024.06.002","article-title":"Cancer treatments: Past, present, and future","volume":"286","author":"Sonkin","year":"2024","journal-title":"Cancer Genet."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"674","DOI":"10.1038\/nrclinonc.2016.66","article-title":"Triple-negative breast cancer: Challenges and opportunities of a heterogeneous disease","volume":"13","author":"Bianchini","year":"2016","journal-title":"Nat. Rev. Clin. Oncol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"49","DOI":"10.1038\/s41392-024-02108-4","article-title":"Breast cancer: Pathogenesis and treatments","volume":"10","author":"Xiong","year":"2025","journal-title":"Signal Transduct. Target. Ther."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"112034","DOI":"10.1016\/j.yexcr.2020.112034","article-title":"BRD4 inhibition suppresses PD-L1 expression in triple-negative breast cancer","volume":"392","author":"Jing","year":"2020","journal-title":"Exp. Cell Res."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"e70733","DOI":"10.1002\/mco2.70733","article-title":"Targeted Therapies for Each Subtype of Breast Cancer","volume":"7","author":"Liu","year":"2026","journal-title":"MedComm"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"107205","DOI":"10.1016\/j.phrs.2024.107205","article-title":"Epigenetic modulations in triple-negative breast cancer: Therapeutic implications for tumor microenvironment","volume":"204","author":"Zhou","year":"2024","journal-title":"Pharmacol. Res."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"422","DOI":"10.1016\/j.semcancer.2021.03.013","article-title":"Current paradigms in epigenetic anticancer therapeutics and future challenges","volume":"83","author":"Singh","year":"2022","journal-title":"Semin. Cancer Biol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"28","DOI":"10.1038\/s41420-024-01803-z","article-title":"Cancer epigenetics: From laboratory studies and clinical trials to precision medicine","volume":"10","author":"Yu","year":"2024","journal-title":"Cell Death Discov."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1783","DOI":"10.1158\/2159-8290.CD-24-0296","article-title":"The epigenetic hallmarks of cancer","volume":"14","author":"Esteller","year":"2024","journal-title":"Cancer Discov."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"156","DOI":"10.1016\/j.phrs.2017.11.015","article-title":"Targeting bromodomain and extraterminal proteins in breast cancer","volume":"129","author":"Sahni","year":"2018","journal-title":"Pharmacol. Res."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"5501","DOI":"10.18632\/oncotarget.3551","article-title":"Inhibition of BET bromodomains as a therapeutic strategy for cancer drug discovery","volume":"6","author":"Fu","year":"2015","journal-title":"Oncotarget"},{"key":"ref_15","doi-asserted-by":"crossref","unstructured":"Khandekar, D., and Tiriveedhi, V. (2020). Role of BET inhibitors in triple negative breast cancers. Cancers, 12.","DOI":"10.3390\/cancers12040784"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"2419","DOI":"10.18632\/oncotarget.1572","article-title":"Inhibition of BET bromodomain proteins as a therapeutic approach in prostate cancer","volume":"4","author":"Wyce","year":"2013","journal-title":"Oncotarget"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"117275","DOI":"10.1016\/j.ejmech.2025.117275","article-title":"Discovery of novel JQ1 derivatives as dual ferroptosis and apoptosis inducers for the treatment of triple-negative breast cancer","volume":"286","author":"Ding","year":"2025","journal-title":"Eur. J. Med. Chem."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"538","DOI":"10.1038\/nature14888","article-title":"BET inhibitor resistance emerges from leukaemia stem cells","volume":"525","author":"Fong","year":"2015","journal-title":"Nature"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1273","DOI":"10.1016\/j.celrep.2016.06.091","article-title":"Resistance to BET bromodomain inhibitors is mediated by kinome reprogramming in ovarian cancer","volume":"16","author":"Kurimchak","year":"2016","journal-title":"Cell Rep."},{"key":"ref_20","doi-asserted-by":"crossref","unstructured":"Yellapu, N.K., Ly, T., Sardiu, M.E., Pei, D., Welch, D.R., Thompson, J.A., and Koestler, D.C. (2022). Synergistic anti-proliferative activity of JQ1 and GSK2801 in triple-negative breast cancer. BMC Cancer, 22.","DOI":"10.1186\/s12885-022-09690-2"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"420","DOI":"10.1038\/s41392-023-01647-6","article-title":"Bromodomain and extraterminal (BET) proteins: Biological functions, diseases and targeted therapy","volume":"8","author":"Wang","year":"2023","journal-title":"Signal Transduct. Target. Ther."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"117875","DOI":"10.1016\/j.bmc.2024.117875","article-title":"Synthesis, SAR, and application of JQ1 analogs as PROTACs for cancer therapy","volume":"112","author":"De","year":"2024","journal-title":"Bioorg. Med. Chem."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"341","DOI":"10.1038\/s41571-020-0333-y","article-title":"Tissue-resident memory T cells in breast cancer control and immunotherapy responses","volume":"17","author":"Byrne","year":"2020","journal-title":"Nat. Rev. Clin. Oncol."},{"key":"ref_24","doi-asserted-by":"crossref","unstructured":"Yu, J., Guo, Z., and Wang, L. (2023). Progress and challenges of immunotherapy predictive biomarkers for triple negative breast cancer in the era of single-cell multi-omics. Life, 13.","DOI":"10.3390\/life13051189"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"554","DOI":"10.1038\/s41568-024-00714-6","article-title":"Towards targeting the breast cancer immune microenvironment","volume":"24","author":"Harris","year":"2024","journal-title":"Nat. Rev. Cancer"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"646","DOI":"10.1016\/j.cell.2011.02.013","article-title":"Hallmarks of cancer: The next generation","volume":"144","author":"Hanahan","year":"2011","journal-title":"Cell"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"2564","DOI":"10.7150\/thno.45280","article-title":"IL20RA signaling enhances stemness and promotes the formation of an immunosuppressive microenvironment in breast cancer","volume":"11","author":"Gao","year":"2021","journal-title":"Theranostics"},{"key":"ref_28","doi-asserted-by":"crossref","unstructured":"Maggisano, V., D\u2019Amico, M., Aquila, S., Giordano, F., Battaglia, A.M., Chimento, A., Biamonte, F., Russo, D., Pezzi, V., and Bulotta, S. (2025). IL-20 Subfamily Biological Effects: Mechanistic Insights and Therapeutic Perspectives in Cancer. Int. J. Mol. Sci., 26.","DOI":"10.3390\/ijms26157320"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"736","DOI":"10.1038\/nrc3818","article-title":"Revisiting STAT3 signalling in cancer: New and unexpected biological functions","volume":"14","author":"Yu","year":"2014","journal-title":"Nat. Rev. Cancer"},{"key":"ref_30","doi-asserted-by":"crossref","unstructured":"Yu, D., Yang, X., Lin, J., Cao, Z., Lu, C., Yang, Z., Zheng, M., Pan, R., and Cai, W. (2021). Super-enhancer induced IL-20RA promotes proliferation\/metastasis and immune evasion in colorectal cancer. Front. Oncol., 11.","DOI":"10.3389\/fonc.2021.724655"},{"key":"ref_31","doi-asserted-by":"crossref","unstructured":"Maggisano, V., Celano, M., Malivindi, R., Barone, I., Cosco, D., Mio, C., Mignogna, C., Panza, S., Damante, G., and Fresta, M. (2019). Nanoparticles loaded with the BET inhibitor JQ1 block the growth of triple negative breast cancer cells in vitro and in vivo. Cancers, 12.","DOI":"10.3390\/cancers12010091"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"347","DOI":"10.1038\/s41571-018-0001-7","article-title":"Triple-negative breast cancers\u2014A panoply of cancer types","volume":"15","author":"Pareja","year":"2018","journal-title":"Nat. Rev. Clin. Oncol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"933","DOI":"10.1158\/2159-8290.CD-20-1808","article-title":"Therapeutic targeting of the tumor microenvironment","volume":"11","author":"Bejarano","year":"2021","journal-title":"Cancer Discov."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"783","DOI":"10.1038\/nri3766","article-title":"The IL-20 subfamily of cytokines\u2014From host defence to tissue homeostasis","volume":"14","author":"Rutz","year":"2014","journal-title":"Nat. Rev. Immunol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"3293","DOI":"10.1158\/0008-5472.CAN-17-3131","article-title":"IL22RA1\/STAT3 signaling promotes stemness and tumorigenicity in pancreatic cancer","volume":"78","author":"He","year":"2018","journal-title":"Cancer Res."},{"key":"ref_36","doi-asserted-by":"crossref","unstructured":"Maggisano, V., Gargano, A., Maiuolo, J., Ortuso, F., De Amicis, F., Alcaro, S., and Bulotta, S. (2025). Rational identification of Ritonavir as IL-20 receptor A ligand endowed with antiproliferative properties in breast cancer cells. Int. J. Mol. Sci., 26.","DOI":"10.3390\/ijms26031285"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"1908","DOI":"10.1016\/j.ejca.2011.04.012","article-title":"IL-20 is epigenetically regulated in NSCLC and down regulates the expression of VEGF","volume":"47","author":"Baird","year":"2011","journal-title":"Eur. J. Cancer"},{"key":"ref_38","doi-asserted-by":"crossref","unstructured":"Mio, C., Bulotta, S., Russo, D., and Damante, G. (2019). Reading cancer: Chromatin readers as druggable targets for cancer treatment. Cancers, 11.","DOI":"10.3390\/cancers11010061"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"76","DOI":"10.1016\/j.drudis.2017.09.011","article-title":"Targeting the cancer epigenome: Synergistic therapy with bromodomain inhibitors","volume":"23","author":"Ramadoss","year":"2018","journal-title":"Drug Discov. Today"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"e13730","DOI":"10.1111\/cpr.13730","article-title":"BET inhibitors (BETi) influence oxidative phosphorylation metabolism by affecting mitochondrial dynamics leading to alterations in apoptotic pathways in triple-negative breast cancer (TNBC) cells","volume":"57","author":"Rossi","year":"2024","journal-title":"Cell Prolif."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"152","DOI":"10.1016\/j.breast.2020.08.005","article-title":"The emerging role of BET inhibitors in breast cancer","volume":"53","author":"Andrikopoulou","year":"2020","journal-title":"Breast"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"33623","DOI":"10.18632\/oncotarget.5601","article-title":"Induction of USP17 by combining BET and HDAC inhibitors in breast cancer cells","volume":"6","author":"Borbely","year":"2015","journal-title":"Oncotarget"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"1304","DOI":"10.1158\/1535-7163.MCT-23-0303","article-title":"Combination therapies to improve the efficacy of immunotherapy in triple-negative breast cancer","volume":"22","author":"Li","year":"2023","journal-title":"Mol. Cancer Ther."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"371","DOI":"10.1080\/13543776.2025.2463150","article-title":"A patent review of BRD4 inhibitors (2020\u2013present)","volume":"35","author":"Chen","year":"2025","journal-title":"Expert Opin. Ther. Pat."},{"key":"ref_45","doi-asserted-by":"crossref","unstructured":"Celano, M., Gagliardi, A., Maggisano, V., Ambrosio, N., Bulotta, S., Fresta, M., Russo, D., and Cosco, D. (2022). Co-encapsulation of paclitaxel and JQ1 in Zein nanoparticles as potential innovative nanomedicine. Micromachines, 13.","DOI":"10.3390\/mi13101580"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"8319","DOI":"10.1007\/s11033-023-08718-5","article-title":"Effects of bromodomain and extra-terminal inhibitor JQ1 and interleukin-6 on breast cancer cells","volume":"50","author":"Sharifhoseini","year":"2023","journal-title":"Mol. Biol. Rep."},{"key":"ref_47","doi-asserted-by":"crossref","unstructured":"Huang, B., Lang, X., and Li, X. (2022). The role of IL-6\/JAK2\/STAT3 signaling pathway in cancers. Front. Oncol., 12.","DOI":"10.3389\/fonc.2022.1023177"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"178079","DOI":"10.1016\/j.ejphar.2025.178079","article-title":"Targeting STAT3 pathway: A promising immunotherapeutic strategy for triple-negative breast cancer\u2013Current status and future outlooks","volume":"1005","author":"Malekinejad","year":"2025","journal-title":"Eur. J. Pharmacol."},{"key":"ref_49","doi-asserted-by":"crossref","unstructured":"Dong, P., Xiong, Y., Yue, J., Hanley, S.J., and Watari, H. (2018). Tumor-intrinsic PD-L1 signaling in cancer initiation, development and treatment: Beyond immune evasion. Front. Oncol., 8.","DOI":"10.3389\/fonc.2018.00386"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"10","DOI":"10.3892\/ol.2022.13596","article-title":"Research progress on the intrinsic non-immune function of PD-L1 in tumors","volume":"25","author":"Deng","year":"2022","journal-title":"Oncol. Lett."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"111436","DOI":"10.1016\/j.biopha.2021.111436","article-title":"PD-L1 silencing inhibits triple-negative breast cancer development and upregulates T-cell-induced pro-inflammatory cytokines","volume":"138","author":"Lotfinejad","year":"2021","journal-title":"Biomed. Pharmacother."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"1187","DOI":"10.1158\/1535-7163.MCT-17-0559","article-title":"Anti-hTERT siRNA-loaded nanoparticles block the growth of anaplastic thyroid cancer xenograft","volume":"17","author":"Lombardo","year":"2018","journal-title":"Mol. Cancer Ther."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"1328","DOI":"10.1016\/j.ajpath.2015.12.024","article-title":"Glucocorticoid receptor as a potential target to decrease aromatase expression and inhibit Leydig tumor growth","volume":"186","author":"Panza","year":"2016","journal-title":"Am. J. Pathol."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/27\/12\/5233\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,6,17]],"date-time":"2026-06-17T04:14:16Z","timestamp":1781669656000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/27\/12\/5233"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,6,9]]},"references-count":53,"journal-issue":{"issue":"12","published-online":{"date-parts":[[2026,6]]}},"alternative-id":["ijms27125233"],"URL":"https:\/\/doi.org\/10.3390\/ijms27125233","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,6,9]]}}}