{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,22]],"date-time":"2026-10-22T16:24:32Z","timestamp":1792686272370,"version":"4.5.0"},"reference-count":38,"publisher":"National Academy of Sciences","issue":"29","content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2004,7,20]]},"abstract":"<jats:p>\n                    Fatty acid synthase (FAS) activity is a potential therapeutic target to treat cancer and obesity. Here, we have identified a molecular link between FAS and\n                    <jats:italic>HER2<\/jats:italic>\n                    (\n                    <jats:italic>erb<\/jats:italic>\n                    B-2) oncogene, a marker for poor prognosis that is overexpressed in 30% of breast and ovarian cancers. Pharmacological FAS inhibitors cerulenin and C75 were found to suppress p185\n                    <jats:italic>\n                      <jats:sup>HER2<\/jats:sup>\n                    <\/jats:italic>\n                    oncoprotein expression and tyrosine-kinase activity in breast and ovarian\n                    <jats:italic>HER2<\/jats:italic>\n                    overexpressors. Similarly, p185\n                    <jats:italic>\n                      <jats:sup>HER2<\/jats:sup>\n                    <\/jats:italic>\n                    expression was dramatically down-regulated when FAS gene expression was silenced by using the highly sequence-specific mechanism of RNA interference (RNAi). Pharmacological and RNAi-mediated silencing of FAS specifically down-regulated\n                    <jats:italic>HER2<\/jats:italic>\n                    mRNA and, concomitantly, caused a prominent up-regulation of PEA3, a transcriptional repressor of\n                    <jats:italic>HER2<\/jats:italic>\n                    . A cytoplasmic redistribution of p185\n                    <jats:italic>\n                      <jats:sup>HER2<\/jats:sup>\n                    <\/jats:italic>\n                    was associated with marked morphological changes of FAS RNAi-transfected cells, whereas chemical inhibitors of FAS promoted a striking nuclear accumulation of p185\n                    <jats:italic>\n                      <jats:sup>HER2<\/jats:sup>\n                    <\/jats:italic>\n                    . The simultaneous targeting of FAS and\n                    <jats:italic>HER2<\/jats:italic>\n                    by chemical FAS inhibitors and the humanized antibody directed against p185\n                    <jats:italic>\n                      <jats:sup>HER2<\/jats:sup>\n                    <\/jats:italic>\n                    trastuzumab, respectively, was synergistically cytotoxic toward\n                    <jats:italic>HER2<\/jats:italic>\n                    overexpressors. Similarly, concurrent RNAi-mediated silencing of FAS and\n                    <jats:italic>HER2<\/jats:italic>\n                    genes synergistically stimulated apoptotic cell death in\n                    <jats:italic>HER2<\/jats:italic>\n                    overexpressors. p185\n                    <jats:italic>\n                      <jats:sup>HER2<\/jats:sup>\n                    <\/jats:italic>\n                    was synergistically down-regulated after simultaneous inhibition of FAS and\n                    <jats:italic>HER2<\/jats:italic>\n                    by either pharmacological inhibitors or small interfering RNA. These findings provide evidence of an active role of FAS in cancer evolution by specifically regulating oncogenic proteins closely related to malignant transformation, strongly suggesting that\n                    <jats:italic>HER2<\/jats:italic>\n                    oncogene may act as the key molecular sensor of energy imbalance after the perturbation of tumor-associated FAS hyperactivity in cancer cells.\n                  <\/jats:p>","DOI":"10.1073\/pnas.0403390101","type":"journal-article","created":{"date-parts":[[2004,7,2]],"date-time":"2004-07-02T20:42:22Z","timestamp":1088800942000},"page":"10715-10720","update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":292,"title":["Inhibition of fatty acid synthase (FAS) suppresses\n                    <i>HER2\/neu<\/i>\n                    (\n                    <i>erb<\/i>\n                    B-2) oncogene overexpression in cancer cells"],"prefix":"10.1073","volume":"101","author":[{"given":"Javier A.","family":"Menendez","sequence":"first","affiliation":[{"name":"Department of Medicine, Evanston Northwestern Healthcare, 1001 University Place, Evanston, IL 60201; Feinberg School of Medicine, Northwestern University, 303 East Chicago Avenue, Chicago, IL 60611; Cancer Epigenetics Laboratory, Molecular Pathology Program, Spanish National Cancer Center (CNIO), Melchor Fernandez Almagro 3, E-28029, Madrid, Spain; and Institut Catala d'Oncologia, Hospital Universitari Dr. Josep Trueta, Avinguda de Franca s\/n, E-17007 Girona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luciano","family":"Vellon","sequence":"additional","affiliation":[{"name":"Department of Medicine, Evanston Northwestern Healthcare, 1001 University Place, Evanston, IL 60201; Feinberg School of Medicine, Northwestern University, 303 East Chicago Avenue, Chicago, IL 60611; Cancer Epigenetics Laboratory, Molecular Pathology Program, Spanish National Cancer Center (CNIO), Melchor Fernandez Almagro 3, E-28029, Madrid, Spain; and Institut Catala d'Oncologia, Hospital Universitari Dr. Josep Trueta, Avinguda de Franca s\/n, E-17007 Girona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Inderjit","family":"Mehmi","sequence":"additional","affiliation":[{"name":"Department of Medicine, Evanston Northwestern Healthcare, 1001 University Place, Evanston, IL 60201; Feinberg School of Medicine, Northwestern University, 303 East Chicago Avenue, Chicago, IL 60611; Cancer Epigenetics Laboratory, Molecular Pathology Program, Spanish National Cancer Center (CNIO), Melchor Fernandez Almagro 3, E-28029, Madrid, Spain; and Institut Catala d'Oncologia, Hospital Universitari Dr. Josep Trueta, Avinguda de Franca s\/n, E-17007 Girona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bharvi P.","family":"Oza","sequence":"additional","affiliation":[{"name":"Department of Medicine, Evanston Northwestern Healthcare, 1001 University Place, Evanston, IL 60201; Feinberg School of Medicine, Northwestern University, 303 East Chicago Avenue, Chicago, IL 60611; Cancer Epigenetics Laboratory, Molecular Pathology Program, Spanish National Cancer Center (CNIO), Melchor Fernandez Almagro 3, E-28029, Madrid, Spain; and Institut Catala d'Oncologia, Hospital Universitari Dr. Josep Trueta, Avinguda de Franca s\/n, E-17007 Girona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Santiago","family":"Ropero","sequence":"additional","affiliation":[{"name":"Department of Medicine, Evanston Northwestern Healthcare, 1001 University Place, Evanston, IL 60201; Feinberg School of Medicine, Northwestern University, 303 East Chicago Avenue, Chicago, IL 60611; Cancer Epigenetics Laboratory, Molecular Pathology Program, Spanish National Cancer Center (CNIO), Melchor Fernandez Almagro 3, E-28029, Madrid, Spain; and Institut Catala d'Oncologia, Hospital Universitari Dr. Josep Trueta, Avinguda de Franca s\/n, E-17007 Girona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ramon","family":"Colomer","sequence":"additional","affiliation":[{"name":"Department of Medicine, Evanston Northwestern Healthcare, 1001 University Place, Evanston, IL 60201; Feinberg School of Medicine, Northwestern University, 303 East Chicago Avenue, Chicago, IL 60611; Cancer Epigenetics Laboratory, Molecular Pathology Program, Spanish National Cancer Center (CNIO), Melchor Fernandez Almagro 3, E-28029, Madrid, Spain; and Institut Catala d'Oncologia, Hospital Universitari Dr. Josep Trueta, Avinguda de Franca s\/n, E-17007 Girona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ruth","family":"Lupu","sequence":"additional","affiliation":[{"name":"Department of Medicine, Evanston Northwestern Healthcare, 1001 University Place, Evanston, IL 60201; Feinberg School of Medicine, Northwestern University, 303 East Chicago Avenue, Chicago, IL 60611; Cancer Epigenetics Laboratory, Molecular Pathology Program, Spanish National Cancer Center (CNIO), Melchor Fernandez Almagro 3, E-28029, Madrid, Spain; and Institut Catala d'Oncologia, Hospital Universitari Dr. Josep Trueta, Avinguda de Franca s\/n, E-17007 Girona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"341","published-online":{"date-parts":[[2004,7,2]]},"reference":[{"key":"e_1_3_1_1_2","doi-asserted-by":"publisher","DOI":"10.1515\/bchm3.1986.367.2.905"},{"key":"e_1_3_1_2_2","doi-asserted-by":"publisher","DOI":"10.1146\/annurev.nutr.18.1.331"},{"key":"e_1_3_1_3_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.86.4.1188"},{"key":"e_1_3_1_4_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJM198909073211003"},{"key":"e_1_3_1_5_2","doi-asserted-by":"publisher","DOI":"10.1007\/BF00683188"},{"key":"e_1_3_1_6_2","doi-asserted-by":"publisher","DOI":"10.1002\/(SICI)1097-0142(19960201)77:3<474::AID-CNCR8>3.0.CO;2-K"},{"key":"e_1_3_1_7_2","doi-asserted-by":"publisher","DOI":"10.1177\/030089169908500108"},{"key":"e_1_3_1_8_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.91.14.6379"},{"key":"e_1_3_1_9_2","first-page":"2115","volume":"3","year":"1997","unstructured":"Milgraum, L. 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