title: Inhibition of breast cancer progression by a novel histone deacetylase inhibitor, LW479, by down-regulating EGFR expression.
abstract: OBJECTIVE
  Compounds targeting epigenetic events of tumours are likely to be an important addition to anticancer therapy. Histone deacetylase inhibitors (HDACI) have emerged as a promising novel class for therapeutic interventions associated with cancer, and many of them are currently in clinical investigation. Here, we assessed a novel hydroxamate-based HDACI, LW479, in breast cancer progression and explored its underlying mechanism(s).
  
  
  METHODS
  LW479 was identified using the HDACI screening kit. Western blot and flow cytometry were used to analyse the biological effects of LW479 as a novel HDACI. The effects of LW479 were assessed in mouse models of spontaneous and experimental breast cancer. Co-immunoprecipitation, immunofluorescent staining and chromatin immunoprecipitation assays along with immunohistochemical analysis, were used to elucidate the molecular basis of the actions of LW479.
  
  
  RESULTS
  LW479 was identified as a novel HDACI and showed marked cytotoxicity and induced apoptosis, as well as cell cycle arrest, in a panel of breast cancer cell lines. Intraperitoneal injections of LW479 markedly suppressed breast tumour growth and pulmonary metastasis in nude mice. LW479 also decreased levels of EGF receptors (EGFR) by blocking the binding of the transcription factor Sp1 and HDAC1 to the EGFR promoter region.
  
  
  CONCLUSIONS
  Our data have elucidated the mechanisms underlying the inhibition by LW479 of tumour growth and metastasis, in models of breast cancer with aberrant EGFR expression. LW479 could be a candidate drug for breast cancer prevention.
authors.affiliation: Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai, China.
authors.forename: Jingjie
authors.initials: J
authors.lastname: Li
authors.affiliation: Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai, China.|Department of Orthopedics, Shanghai 1st People's Hospital, Shanghai Jiaotong University, Shanghai, China.
authors.forename: Tao
authors.initials: T
authors.lastname: Zhang
authors.affiliation: Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai, China.
authors.forename: Feifei
authors.initials: F
authors.lastname: Yang
authors.affiliation: Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai, China.
authors.forename: Yuan
authors.initials: Y
authors.lastname: He
authors.affiliation: Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai, China.
authors.forename: Fujun
authors.initials: F
authors.lastname: Dai
authors.affiliation: Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai, China.
authors.forename: Dan
authors.initials: D
authors.lastname: Gao
authors.affiliation: Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai, China.
authors.forename: Yihua
authors.initials: Y
authors.lastname: Chen
authors.affiliation: Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai, China.|Center for Cancer and Stem Cell Biology, Institute of Biosciences and Technology, Texas A&M University Health Science Center, Houston, TX, USA.
authors.forename: Mingyao
authors.initials: M
authors.lastname: Liu
authors.affiliation: Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai, China.
authors.forename: Zhengfang
authors.initials: Z
authors.lastname: Yi
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000378:metabolism / Q000473:pathology*; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D018450:Disease Progression; D015536:Down-Regulation / Q000187:drug effects*; D066246:ErbB Receptors / Q000096:biosynthesis* / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology*; D006801:Humans; D006877:Hydroxamic Acids / Q000009:adverse effects / Q000494:pharmacology*; D051379:Mice; D009361:Neoplasm Invasiveness / Q000473:pathology; D011401:Promoter Regions, Genetic / Q000235:genetics; D053778:Thiazolidines / Q000009:adverse effects / Q000494:pharmacology*; D000077337:Vorinostat
chemical_list: C000607980:6-(2-(2-(3-bromophenyl)-4-oxo-3-thiazolidinyl)phenoxy)-N-hydroxylhexanamide; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D053778:Thiazolidines; D000077337:Vorinostat; D066246:ErbB Receptors