{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,25]],"date-time":"2026-09-25T18:39:48Z","timestamp":1790361588512,"version":"4.1.0"},"reference-count":32,"publisher":"MDPI AG","issue":"6","license":[{"start":{"date-parts":[[2026,3,19]],"date-time":"2026-03-19T00:00:00Z","timestamp":1773878400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Nottingham Breast Cancer Research Centre"},{"DOI":"10.13039\/501100022089","name":"University of Botswana","doi-asserted-by":"crossref","id":[{"id":"10.13039\/501100022089","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Upregulation of glutaminase enzymatic activity promotes tumour cell proliferation. Its overexpression correlates with poor disease outcome in patients, including those with breast cancer. A selective glutaminase inhibitor, CB-839, which targets cancer cells by blocking glutamine conversion to glutamate, has shown promising preclinical results as a therapeutic target in triple-negative breast cancer treatment. The current study aimed to determine the importance of glutaminase in Oestrogen Receptor positive\/luminal breast cancer to potentially identify therapeutic targets to treat this subtype. In vitro studies using luminal breast cancer cells were performed to investigate the effects of siRNA knockdown of glutaminase genes (GLS and GLS2) and inhibition using CB-839 on functional assays. Silencing GLS in luminal breast cancer cells significantly reduced cell proliferation whilst inducing apoptosis. A similar impact on cell proliferation was observed when silencing GLS2 in luminal B cells, but there was no observed effect on cell apoptosis and cell cycle. There was little effect of GLS inhibition using CB-839 in luminal breast cancer. This study demonstrates that glutaminase is necessary for luminal breast cancer growth and survival. Co-targeting GLS and GLS2 might be a novel approach for the treatment of this subclass. Further functional studies to evaluate the underlying molecular mechanisms of this process are warranted.<\/jats:p>","DOI":"10.3390\/ijms27062780","type":"journal-article","created":{"date-parts":[[2026,3,19]],"date-time":"2026-03-19T08:54:37Z","timestamp":1773910477000},"page":"2780","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Targeting Glutaminase Isoforms GLS and GLS2 in Luminal Breast Cancer"],"prefix":"10.3390","volume":"27","author":[{"given":"Brendah K.","family":"Masisi","sequence":"first","affiliation":[{"name":"Nottingham Breast Cancer Research Centre, Academic Unit for Translational Medical Sciences, School of Medicine, University of Nottingham Biodiscovery Institute, University Park, Nottingham NG7 2RD, UK"},{"name":"School of Allied Health Professions, Faculty of Health Sciences, University of Botswana, Plot 4775 Notwane and Mobuto Road, Gaborone P\/Bag UB 0022, Botswana"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rokaya","family":"El Ansari","sequence":"additional","affiliation":[{"name":"Nottingham Breast Cancer Research Centre, Academic Unit for Translational Medical Sciences, School of Medicine, University of Nottingham Biodiscovery Institute, University Park, Nottingham NG7 2RD, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ali","family":"Fakroun","sequence":"additional","affiliation":[{"name":"Nottingham Breast Cancer Research Centre, Academic Unit for Translational Medical Sciences, School of Medicine, University of Nottingham Biodiscovery Institute, University Park, Nottingham NG7 2RD, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"B\u00fcsra","family":"Erkan","sequence":"additional","affiliation":[{"name":"Nottingham Breast Cancer Research Centre, Academic Unit for Translational Medical Sciences, School of Medicine, University of Nottingham Biodiscovery Institute, University Park, Nottingham NG7 2RD, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emad A.","family":"Rakha","sequence":"additional","affiliation":[{"name":"Nottingham Breast Cancer Research Centre, Academic Unit for Translational Medical Sciences, School of Medicine, University of Nottingham Biodiscovery Institute, University Park, Nottingham NG7 2RD, UK"},{"name":"Department of Cellular Pathology, Nottingham University Hospitals NHS Trust, Nottingham City Hospital, Hucknall Road, Nottingham NG5 1PB, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0488-5913","authenticated-orcid":false,"given":"Andrew R.","family":"Green","sequence":"additional","affiliation":[{"name":"Nottingham Breast Cancer Research Centre, Academic Unit for Translational Medical Sciences, School of Medicine, University of Nottingham Biodiscovery Institute, University Park, Nottingham NG7 2RD, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,3,19]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"617","DOI":"10.1038\/emboj.2013.19","article-title":"A new genome-driven integrated classification of breast cancer and its implications","volume":"32","author":"Dawson","year":"2013","journal-title":"EMBO J."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"2794","DOI":"10.1200\/JCO.2013.54.1870","article-title":"Luminal B breast cancer: Molecular characterization, clinical management, and future perspectives","volume":"32","author":"Ades","year":"2014","journal-title":"J. Clin. Oncol."},{"key":"ref_3","doi-asserted-by":"crossref","unstructured":"Early Breast Cancer Trialists\u2019 Collaborative Group (EBCTCG), Davies, C., Godwin, J., Gray, R., Clarke, M., Cutter, D., Darby, S., McGale, P., Pan, H.C., and Taylor, C. (2011). Relevance of breast cancer hormone receptors and other factors to the efficacy of adjuvant tamoxifen: Patient-level meta-analysis of randomised trials. Lancet, 378, 771\u2013784.","DOI":"10.1016\/S0140-6736(11)60993-8"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"220","DOI":"10.1016\/j.mce.2015.09.035","article-title":"Endocrine resistance in breast cancer\u2014An overview and update","volume":"418","author":"Clarke","year":"2015","journal-title":"Mol. Cell. Endocrinol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1979","DOI":"10.1200\/JCO.2014.55.4139","article-title":"Past, present, and future challenges in breast cancer treatment","volume":"32","author":"Sledge","year":"2014","journal-title":"J. Clin. Oncol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"15330338221090351","DOI":"10.1177\/15330338221090351","article-title":"Estrogen receptor bio-activities determine clinical endocrine treatment options in estrogen receptor-positive breast cancer","volume":"21","author":"Xia","year":"2022","journal-title":"Technol. Cancer Res. Treat."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"351","DOI":"10.1038\/ncb3124","article-title":"Metabolic pathways promoting cancer cell survival and growth","volume":"17","author":"Boroughs","year":"2015","journal-title":"Nat. Cell Biol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"163","DOI":"10.1146\/annurev-bioeng-071516-044546","article-title":"Glutaminolysis: A hallmark of cancer metabolism","volume":"19","author":"Yang","year":"2017","journal-title":"Annu. Rev. Biomed. Eng."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"223","DOI":"10.4155\/fmc-2016-0190","article-title":"A tale of two glutaminases: Homologous enzymes with distinct roles in tumorigenesis","volume":"9","author":"Katt","year":"2017","journal-title":"Future Med. Chem."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"498","DOI":"10.1111\/his.14014","article-title":"The role of glutaminase in cancer","volume":"76","author":"Masisi","year":"2020","journal-title":"Histopathology"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"514","DOI":"10.2174\/1566524011313040005","article-title":"Glutaminase isoenzymes as key regulators in metabolic and oxidative stress against cancer","volume":"13","author":"Mates","year":"2013","journal-title":"Curr. Mol. Med."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"450","DOI":"10.1016\/j.drudis.2013.10.008","article-title":"Glutaminase regulation in cancer cells: A druggable chain of events","volume":"19","author":"Katt","year":"2014","journal-title":"Drug Discov. Today"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1005","DOI":"10.2967\/jnumed.110.084244","article-title":"Role of glutamine in cancer: Therapeutic and imaging implications","volume":"52","author":"Rajagopalan","year":"2011","journal-title":"J. Nucl. Med."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1007\/s10549-018-05111-w","article-title":"The combined expression of solute carriers is associated with a poor prognosis in highly proliferative ER+ breast cancer","volume":"175","author":"Craze","year":"2019","journal-title":"Breast Cancer Res. Treat."},{"key":"ref_15","doi-asserted-by":"crossref","unstructured":"Masisi, B.K., El Ansari, R., Alfarsi, L., Craze, M.L., Jewa, N., Oldfield, A., Cheung, H., Toss, M., Rakha, E.A., and Green, A.R. (2021). The biological and clinical significance of glutaminase in luminal breast cancer. Cancers, 13.","DOI":"10.3390\/cancers13163963"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"11321","DOI":"10.1038\/ncomms11321","article-title":"The oncogenic transcription factor c-Jun regulates glutaminase expression and sensitizes cells to glutaminase-targeted therapy","volume":"7","author":"Lukey","year":"2016","journal-title":"Nat. Commun."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"76","DOI":"10.1016\/j.celrep.2019.08.076","article-title":"Liver-type glutaminase GLS2 is a druggable metabolic node in luminal-subtype breast cancer","volume":"29","author":"Lukey","year":"2019","journal-title":"Cell Rep."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"890","DOI":"10.1158\/1535-7163.MCT-13-0870","article-title":"Antitumor activity of the glutaminase inhibitor CB-839 in triple-negative breast cancer","volume":"13","author":"Gross","year":"2014","journal-title":"Mol. Cancer Ther."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1855","DOI":"10.1007\/s13277-013-1247-4","article-title":"Silencing of GLS and overexpression of GLS2 genes cooperate in decreasing the proliferation and viability of glioblastoma cells","volume":"35","author":"Szeliga","year":"2014","journal-title":"Tumor Biol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"104536","DOI":"10.1016\/j.esmoop.2025.104536","article-title":"A phase I\/II study of the safety and efficacy of telaglenastat (CB-839) in combination with nivolumab in patients with metastatic melanoma, renal cell carcinoma, and non-small-cell lung cancer","volume":"10","author":"Gouda","year":"2025","journal-title":"ESMO Open"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"207","DOI":"10.1016\/j.ccr.2010.08.009","article-title":"Targeting mitochondrial glutaminase activity inhibits oncogenic transformation","volume":"18","author":"Wang","year":"2010","journal-title":"Cancer Cell"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"258","DOI":"10.1038\/bjc.2017.387","article-title":"MYC regulation of glutamine\u2013proline regulatory axis is key in luminal B breast cancer","volume":"118","author":"Craze","year":"2018","journal-title":"Br. J. Cancer"},{"key":"ref_23","doi-asserted-by":"crossref","unstructured":"Saha, S.K., Islam, S.R., Abdullah-Al-Wadud, M., Islam, S., Ali, F., and Park, K.S. (2019). Multiomics analysis reveals that GLS and GLS2 differentially modulate the clinical outcomes of cancer. J. Clin. Med., 8.","DOI":"10.3390\/jcm8030355"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"158","DOI":"10.1016\/j.bbcan.2018.07.007","article-title":"Glutaminase isoenzymes in the metabolic therapy of cancer","volume":"1870","year":"2018","journal-title":"Biochim. Biophys. Acta (BBA)-Rev. Cancer"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"395","DOI":"10.1038\/s41420-021-00792-7","article-title":"Mitochondrial glutamine metabolism regulates sensitivity of cancer cells after chemotherapy via amphiregulin","volume":"7","author":"Hwang","year":"2021","journal-title":"Cell Death Discov."},{"key":"ref_26","doi-asserted-by":"crossref","unstructured":"Lampa, M., Arlt, H., He, T., Ospina, B., Reeves, J., Zhang, B., Murtie, J., Deng, G., Barberis, C., and Hoffmann, D. (2017). Glutaminase is essential for the growth of triple-negative breast cancer cells with a deregulated glutamine metabolism pathway and its suppression synergizes with mTOR inhibition. PLoS ONE, 12.","DOI":"10.1371\/journal.pone.0185092"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"102231","DOI":"10.1016\/j.cbpa.2022.102231","article-title":"Substrate-selective small-molecule modulators of enzymes: Mechanisms and opportunities","volume":"72","author":"Lin","year":"2023","journal-title":"Curr. Opin. Chem. Biol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"e10727","DOI":"10.7554\/eLife.10727","article-title":"Glutaminase 2 is a novel negative regulator of small GTPase Rac1 and mediates p53 function in suppressing metastasis","volume":"5","author":"Zhang","year":"2016","journal-title":"eLife"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"12221","DOI":"10.1038\/s41598-017-12557-3","article-title":"Glutaminase 2 expression is associated with regional heterogeneity of 5-aminolevulinic acid fluorescence in glioblastoma","volume":"7","author":"Kim","year":"2017","journal-title":"Sci. Rep."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"7461","DOI":"10.1073\/pnas.1002459107","article-title":"Phosphate-activated glutaminase (GLS2), a p53-inducible regulator of glutamine metabolism and reactive oxygen species","volume":"107","author":"Suzuki","year":"2010","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"34","DOI":"10.1016\/j.semcdb.2019.05.012","article-title":"Therapeutic targeting of glutaminolysis as an essential strategy to combat cancer","volume":"98","author":"Mazurek","year":"2020","journal-title":"Semin. Cell Dev. Biol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"3131","DOI":"10.7150\/jca.18457","article-title":"Breast cancer cell line classification and its relevance with breast tumor subtyping","volume":"8","author":"Dai","year":"2017","journal-title":"J. Cancer"}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/27\/6\/2780\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,3,21]],"date-time":"2026-03-21T05:20:26Z","timestamp":1774070426000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/27\/6\/2780"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,3,19]]},"references-count":32,"journal-issue":{"issue":"6","published-online":{"date-parts":[[2026,3]]}},"alternative-id":["ijms27062780"],"URL":"https:\/\/doi.org\/10.3390\/ijms27062780","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,3,19]]}}}