title: Prolyl-isomerase Pin1 impairs trastuzumab sensitivity by up-regulating fatty acid synthase expression.
abstract: OBJECTIVE
  Clinical trials have shown efficacy of the anti-HER2 monoclonal antibody trastuzumab in metastatic breast cancer patients. The aim of the present study was to elucidate the mechanisms by which up-regulation of fatty acid synthase (FAS) expression confers resistance to trastuzumab in HER2-positive breast cancers.
  
  
  METHODS
  The expression of FAS as well as the cytotoxic effects of combinatorial treatment of trastuzumab and juglone was investigated by immunoblotting, BrdU incorporation, TUNEL assay, and soft agar assay.
  
  
  RESULTS
  Pin1 enhanced EGF-induced SREBP1c promoter activity, resulting in the induction of FAS expression in BT474 cells. In contrast, juglone, a potent Pin1 inhibitor, significantly enhanced trastuzumab-induced FAS down-regulation and cell death in BT474 cells. Furthermore, trastuzumab, when used in combination with gene silencing or chemical inhibition of Pin1, increased cleaved poly(ADP-ribose) polymerase and DNA fragmentation to increase trastuzumab sensitivity.
  
  
  CONCLUSIONS
  Pin1-mediated FAS overexpression is a major regulator of trastuzumab-resistant breast cancer growth and survival.
authors.affiliation: College of Pharmacy, Chosun University, 309 Pilmun-daero, Dong-gu, Gwangju 501-759 Korea, chs@chosun.ac.kr.
authors.forename: Hyo Jeong
authors.initials: HJ
authors.lastname: Yun
authors.forename: Jin Young
authors.initials: JY
authors.lastname: Kim
authors.forename: Garam
authors.initials: G
authors.lastname: Kim
authors.forename: Hong Seok
authors.initials: HS
authors.lastname: Choi
mesh_terms: D000818:Animals; D061067:Antibodies, Monoclonal, Humanized / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism* / Q000473:pathology; D002448:Cell Adhesion / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002471:Cell Transformation, Neoplastic / Q000187:drug effects / Q000473:pathology; D004815:Epidermal Growth Factor / Q000494:pharmacology; D064429:Fatty Acid Synthases / Q000378:metabolism*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D000072340:NIMA-Interacting Peptidylprolyl Isomerase; D019696:Peptidylprolyl Isomerase / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D011401:Promoter Regions, Genetic / Q000235:genetics; D034741:RNA, Small Interfering / Q000235:genetics; D051780:Sterol Regulatory Element Binding Protein 1 / Q000378:metabolism; D000068878:Trastuzumab; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D000072340:NIMA-Interacting Peptidylprolyl Isomerase; D034741:RNA, Small Interfering; C497387:SREBF1 protein, human; D051780:Sterol Regulatory Element Binding Protein 1; D004815:Epidermal Growth Factor; D064429:Fatty Acid Synthases; C000606846:PIN1 protein, human; D019696:Peptidylprolyl Isomerase; C000606850:Pin1 protein, mouse; D000068878:Trastuzumab
keywords: FAS; HER2; Pin1; Trastuzumab; chemoresistance