{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,24]],"date-time":"2026-08-24T15:17:54Z","timestamp":1787584674818,"version":"build-2736575974"},"reference-count":36,"publisher":"National Academy of Sciences","issue":"42","license":[{"start":{"date-parts":[[2023,10,10]],"date-time":"2023-10-10T00:00:00Z","timestamp":1696896000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100004802","name":"California Breast Cancer Research Program","doi-asserted-by":"publisher","award":["22OB-0032"],"award-info":[{"award-number":["22OB-0032"]}],"id":[{"id":"10.13039\/100004802","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000054","name":"HHS | NIH | National Cancer Institute","doi-asserted-by":"publisher","award":["1R35CA197694-01"],"award-info":[{"award-number":["1R35CA197694-01"]}],"id":[{"id":"10.13039\/100000054","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000289","name":"Cancer Research UK","doi-asserted-by":"publisher","award":["A27145"],"award-info":[{"award-number":["A27145"]}],"id":[{"id":"10.13039\/501100000289","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2023,10,17]]},"abstract":"<jats:p>Although robustly expressed in the disease-free (DF) breast stroma, CD36 is consistently absent from the stroma surrounding invasive breast cancers (IBCs). In this study, we primarily observed CD36 expression in adipocytes and intralobular capillaries within the DF breast. Larger vessels concentrated in interlobular regions lacked CD36 and were instead marked by the expression of CD31. When evaluated in perilesional capillaries surrounding ductal carcinoma in situ, a nonobligate IBC precursor, CD36 loss was more commonly observed in lesions associated with subsequent IBC. Peroxisome proliferator-activated receptor \u03b3 (PPAR\u03b3) governs the expression of CD36 and genes involved in differentiation, metabolism, angiogenesis, and inflammation. Coincident with CD36 loss, we observed a dramatic suppression of PPAR\u03b3 and its target genes in capillary endothelial cells (ECs) and pericytes, which typically surround and support the stability of the capillary endothelium. Factors present in conditioned media from malignant cells repressed PPAR\u03b3 and its target genes not only in cultured ECs and pericytes but also in adipocytes, which require PPAR\u03b3 for proper differentiation. In addition, we identified a role for PPAR\u03b3 in opposing the transition of pericytes toward a tumor-supportive myofibroblast phenotype. In mouse xenograft models, early intervention with rosiglitazone, a PPAR\u03b3 agonist, demonstrated significant antitumor effects; however, following the development of a palpable tumor, the antitumor effects of rosiglitazone were negated by the repression of PPAR\u03b3 in the mouse stroma. In summary, PPAR\u03b3 activity in healthy tissues places several stromal cell types in an antitumorigenic state, directly inhibiting EC proliferation, maintaining adipocyte differentiation, and suppressing the transition of pericytes into tumor-supportive myofibroblasts.<\/jats:p>","DOI":"10.1073\/pnas.2303774120","type":"journal-article","created":{"date-parts":[[2023,10,10]],"date-time":"2023-10-10T13:42:03Z","timestamp":1696945323000},"update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":17,"title":["Loss of PPAR\u03b3 activity characterizes early protumorigenic stromal reprogramming and dictates the therapeutic window of opportunity"],"prefix":"10.1073","volume":"120","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4043-3762","authenticated-orcid":false,"given":"Joseph A.","family":"Caruso","sequence":"first","affiliation":[{"name":"Department of Pathology, University of California, San Francisco, CA 94143"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xianhong","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Pathology, University of California, San Francisco, CA 94143"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lyndsay M.","family":"Murrow","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Chemistry, University of California, San Francisco, CA 94143"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4325-6132","authenticated-orcid":false,"given":"Carlos Ivan","family":"Rodriguez","sequence":"additional","affiliation":[{"name":"Department of Pathology, University of California, San Francisco, CA 94143"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chira","family":"Chen-Tanyolac","sequence":"additional","affiliation":[{"name":"Department of Pathology, University of California, San Francisco, CA 94143"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lisa","family":"Vu","sequence":"additional","affiliation":[{"name":"Department of Medicine and Epidemiology and Biostatistics, University of California, San Francisco, CA 94143"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yunn-Yi","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Pathology, University of California, San Francisco, CA 94143"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5912-5228","authenticated-orcid":false,"given":"Philippe","family":"Gascard","sequence":"additional","affiliation":[{"name":"Department of Pathology, University of California, San Francisco, CA 94143"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zev J.","family":"Gartner","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Chemistry, University of California, San Francisco, CA 94143"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8793-8779","authenticated-orcid":false,"given":"Karla","family":"Kerlikowske","sequence":"additional","affiliation":[{"name":"Department of Medicine and Epidemiology and Biostatistics, University of California, San Francisco, CA 94143"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thea D.","family":"Tlsty","sequence":"additional","affiliation":[{"name":"Department of Pathology, University of California, San Francisco, CA 94143"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"341","published-online":{"date-parts":[[2023,10,10]]},"reference":[{"key":"e_1_3_4_1_2","doi-asserted-by":"publisher","DOI":"10.1158\/2159-8290.CD-12-0107"},{"key":"e_1_3_4_2_2","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-13-3390"},{"key":"e_1_3_4_3_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.274.27.19055"},{"key":"e_1_3_4_4_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M003826200"},{"key":"e_1_3_4_5_2","doi-asserted-by":"publisher","DOI":"10.1083\/jcb.138.3.707"},{"key":"e_1_3_4_6_2","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2013-01-482315"},{"key":"e_1_3_4_7_2","doi-asserted-by":"publisher","DOI":"10.1038\/2030"},{"key":"e_1_3_4_8_2","doi-asserted-by":"publisher","DOI":"10.1016\/S1097-2765(00)80047-7"},{"key":"e_1_3_4_9_2","doi-asserted-by":"publisher","DOI":"10.1172\/JCI0215634"},{"key":"e_1_3_4_10_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.274.13.9116"},{"key":"e_1_3_4_11_2","doi-asserted-by":"publisher","DOI":"10.1152\/ajplung.00333.2007"},{"key":"e_1_3_4_12_2","doi-asserted-by":"publisher","DOI":"10.1038\/s42255-018-0008-5"},{"key":"e_1_3_4_13_2","doi-asserted-by":"publisher","DOI":"10.1093\/carcin\/bgs173"},{"key":"e_1_3_4_14_2","doi-asserted-by":"publisher","DOI":"10.1007\/s00592-013-0504-8"},{"key":"e_1_3_4_15_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cels.2022.06.005"},{"key":"e_1_3_4_16_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-022-33052-y"},{"key":"e_1_3_4_17_2","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-03-1957"},{"key":"e_1_3_4_18_2","doi-asserted-by":"publisher","DOI":"10.1172\/jci.insight.91738"},{"key":"e_1_3_4_19_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-020-17740-1"},{"key":"e_1_3_4_20_2","doi-asserted-by":"publisher","DOI":"10.1093\/jnci\/djq101"},{"key":"e_1_3_4_21_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.272.8.5128"},{"key":"e_1_3_4_22_2","doi-asserted-by":"publisher","DOI":"10.1042\/BCJ20160943"},{"key":"e_1_3_4_23_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbalip.2013.02.010"},{"key":"e_1_3_4_24_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbrc.2014.01.077"},{"key":"e_1_3_4_25_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1608384113"},{"key":"e_1_3_4_26_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.devcel.2006.01.015"},{"key":"e_1_3_4_27_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ccr.2008.03.007"},{"key":"e_1_3_4_28_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2022.111362"},{"key":"e_1_3_4_29_2","doi-asserted-by":"publisher","DOI":"10.1038\/nature03988"},{"key":"e_1_3_4_30_2","doi-asserted-by":"publisher","DOI":"10.1006\/exmp.2002.2424"},{"key":"e_1_3_4_31_2","doi-asserted-by":"publisher","DOI":"10.1369\/jhc.4A6514.2005"},{"key":"e_1_3_4_32_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.tcb.2017.12.002"},{"key":"e_1_3_4_33_2","doi-asserted-by":"publisher","DOI":"10.2353\/ajpath.2008.080433"},{"key":"e_1_3_4_34_2","unstructured":"C. Tabula Sapiens The Tabula Sapiens: A multiple-organ single-cell transcriptomic atlas of humans. Science 376 eabl4896 (2022). eabl4896"},{"key":"e_1_3_4_35_2","doi-asserted-by":"publisher","DOI":"10.1023\/A:1024038127156"},{"key":"e_1_3_4_36_2","unstructured":"T. Tlsty J. Caruso scRNA-seq profiling of vascular cells isolated from disease-free human breast based on the expression of CD36 and\/or CD31. Gene Expression Omnibus. https:\/\/www.ncbi.nlm.nih.gov\/geo\/query\/acc.cgi?acc=GSE190592. Deposited 9 December 2021."}],"container-title":["Proceedings of the National Academy of Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/pnas.org\/doi\/pdf\/10.1073\/pnas.2303774120","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,10,10]],"date-time":"2023-10-10T13:42:49Z","timestamp":1696945369000},"score":1,"resource":{"primary":{"URL":"https:\/\/pnas.org\/doi\/10.1073\/pnas.2303774120"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,10,10]]},"references-count":36,"journal-issue":{"issue":"42","published-print":{"date-parts":[[2023,10,17]]}},"alternative-id":["10.1073\/pnas.2303774120"],"URL":"https:\/\/doi.org\/10.1073\/pnas.2303774120","relation":{},"ISSN":["0027-8424","1091-6490"],"issn-type":[{"value":"0027-8424","type":"print"},{"value":"1091-6490","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,10,10]]},"assertion":[{"value":"2023-03-09","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2023-08-31","order":1,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2023-10-10","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e2303774120"}}