{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,23]],"date-time":"2026-03-23T15:17:45Z","timestamp":1774279065463,"version":"3.50.1"},"reference-count":41,"publisher":"MDPI AG","issue":"10","license":[{"start":{"date-parts":[[2024,5,15]],"date-time":"2024-05-15T00:00:00Z","timestamp":1715731200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"NIH\/NIAID","award":["T32AI106699"],"award-info":[{"award-number":["T32AI106699"]}]},{"name":"NIH\/NIAID","award":["R44CA257278-01A1S1"],"award-info":[{"award-number":["R44CA257278-01A1S1"]}]},{"name":"NIH\/NCI Diversity Supplement Award","award":["T32AI106699"],"award-info":[{"award-number":["T32AI106699"]}]},{"name":"NIH\/NCI Diversity Supplement Award","award":["R44CA257278-01A1S1"],"award-info":[{"award-number":["R44CA257278-01A1S1"]}]},{"name":"Selvaraj and Tirouvanziam labs","award":["T32AI106699"],"award-info":[{"award-number":["T32AI106699"]}]},{"name":"Selvaraj and Tirouvanziam labs","award":["R44CA257278-01A1S1"],"award-info":[{"award-number":["R44CA257278-01A1S1"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Triple-negative breast cancer (TNBC) is an aggressive and highly metastatic type of tumor. TNBC is often enriched in tumor-infiltrating neutrophils (TINs), which support cancer growth in part by counteracting tumor-infiltrating lymphocytes (TILs). Prior studies identified the enhancer of zeste homolog 2 (EZH2) as a pro-tumor methyltransferase in primary and metastatic TNBCs. We hypothesized that EZH2 inhibition in TNBC cells per se would exert antitumor activity by altering the tumor immune microenvironment. To test this hypothesis, we used CRISPR to generate EZH2 gene knockout (KO) and overexpressing (OE) lines from parent (wild-type\u2014WT) 4T1 cells, an established murine TNBC model, resulting in EZH2 protein KO and OE, respectively. In vitro, EZH2 KO and OE cells showed early, transient changes in replicative capacity and invasiveness, and marked changes in surface marker profile and cytokine\/chemokine secretion compared to WT cells. In vivo, EZH2 KO cells showed significantly reduced primary tumor growth and a 10-fold decrease in lung metastasis compared to WT cells, while EZH2 OE cells were unchanged. Compared to WT tumors, TIN:TIL ratios were greatly reduced in EZH2 KO tumors but unchanged in EZH2 OE tumors. Thus, EZH2 is key to 4T1 aggressiveness as its tumor-intrinsic knockout alters their in vitro secretome and in vivo primary tumor growth, TIN\/TIL poise, and metastasis.<\/jats:p>","DOI":"10.3390\/ijms25105392","type":"journal-article","created":{"date-parts":[[2024,5,15]],"date-time":"2024-05-15T06:14:42Z","timestamp":1715753682000},"page":"5392","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Tumor-Intrinsic Enhancer of Zeste Homolog 2 Controls Immune Cell Infiltration, Tumor Growth, and Lung Metastasis in a Triple-Negative Breast Cancer Model"],"prefix":"10.3390","volume":"25","author":[{"given":"Lenore","family":"Monterroza","sequence":"first","affiliation":[{"name":"Department of Pediatrics, Emory University School of Medicine, Atlanta, GA 30322, USA"},{"name":"Department of Pathology & Laboratory Medicine, Emory University School of Medicine, Atlanta, GA 30322, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Maria M.","family":"Parrilla","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Emory University School of Medicine, Atlanta, GA 30322, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7056-5635","authenticated-orcid":false,"given":"Sarah G.","family":"Samaranayake","sequence":"additional","affiliation":[{"name":"MD Program, Emory University School of Medicine, Atlanta, GA 30322, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Dormarie E.","family":"Rivera-Rodriguez","sequence":"additional","affiliation":[{"name":"Department of Microbiology & Immunology, Emory University School of Medicine, Atlanta, GA 30322, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sung Bo","family":"Yoon","sequence":"additional","affiliation":[{"name":"Department of Hematology & Medical Oncology, Emory University School of Medicine, Atlanta, GA 30322, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7367-3159","authenticated-orcid":false,"given":"Ramireddy","family":"Bommireddy","sequence":"additional","affiliation":[{"name":"Department of Pathology & Laboratory Medicine, Emory University School of Medicine, Atlanta, GA 30322, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Justin","family":"Hosten","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Emory University School of Medicine, Atlanta, GA 30322, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Luisa Cervantes","family":"Barragan","sequence":"additional","affiliation":[{"name":"Department of Microbiology & Immunology, Emory University School of Medicine, Atlanta, GA 30322, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Adam","family":"Marcus","sequence":"additional","affiliation":[{"name":"Department of Hematology & Medical Oncology, Emory University School of Medicine, Atlanta, GA 30322, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Brian S.","family":"Dobosh","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Emory University School of Medicine, Atlanta, GA 30322, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3130-0551","authenticated-orcid":false,"given":"Periasamy","family":"Selvaraj","sequence":"additional","affiliation":[{"name":"Department of Pathology & Laboratory Medicine, Emory University School of Medicine, Atlanta, GA 30322, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3526-9985","authenticated-orcid":false,"given":"Rabindra","family":"Tirouvanziam","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Emory University School of Medicine, Atlanta, GA 30322, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2024,5,15]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"15","DOI":"10.1016\/j.breast.2022.08.010","article-title":"Current and future burden of breast cancer: Global statistics for 2020 and 2040","volume":"66","author":"Arnold","year":"2022","journal-title":"Breast"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"95","DOI":"10.1038\/s41523-022-00468-0","article-title":"Triple negative breast cancer: Pitfalls and progress","volume":"8","author":"Zagami","year":"2022","journal-title":"NPJ Breast Cancer"},{"key":"ref_3","first-page":"001","article-title":"Triple Negative Breast Cancer\u2014An Overview","volume":"2013","author":"Aysola","year":"2013","journal-title":"Hered. 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