title: Identification of a novel inhibitor of triple-negative breast cancer cell growth by screening of a small-molecule library.
abstract: BACKGROUND
  Triple-negative breast cancers (TNBC) are defined as not having amplification of the estrogen receptor, progesterone receptor, or epidermal growth factor receptor 2. Recovery of patients is, currently, severely limited after diagnosis of metastatic TNBC, with fewer than 30 % of patients surviving more than 5 years. The most effective therapy to date is chemotherapy, which has been unsuccessful because of lack of therapeutic targets for these aggressive cancers. To identify new molecular targets for TNBC, we have developed a novel method for drug discovery using active compounds for identification of pharmacodynamic biomarkers.
  
  
  METHODS
  We used chemical informatics to design a small-molecule library with structural diversity. This library was used to screen for compounds that selectively inhibit proliferation of TNBC cell lines. Different gene-expression profiles in cell lines before and after the addition of selected compounds were analyzed and compared with those of control cells.
  
  
  RESULTS
  We identified (E)-3-(3,4-dihydroxybenzylidene)benzofuran-2(3H)-one (DBBF) which specifically inhibited proliferation of a TNBC cell line, MDA-MB-468, with an IC50 of 2.4 μM. Microarray analysis identified several signaling pathways, including the irinotecan pathway, which changed specifically in the TNBC cell lines on addition of DBBF.
  
  
  CONCLUSIONS
  We have developed a novel research strategy that involves screening of selective inhibitors of TNBC cell line proliferation that can be used for identification of pharmacodynamic biomarkers for TNBC. The discovery of new pathways by this technique should lead to the identification of new therapeutic targets for this aggressive cancer.
authors: Department of Breast Surgery, Tokyo Medical University Ibaraki Medical Center, 3-20-1 Chuo, Ami Inashiki, Ibaraki, 300-0395, Japan.
authors: Tomoyuki
authors: T
authors: Fujita
authors: Tamio
authors: T
authors: Mizukami
authors: Tadashi
authors: T
authors: Okawara
authors: Kengo
authors: K
authors: Inoue
authors: Minoru
authors: M
authors: Fujimori
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D001572:Benzofurans / Q000494:pharmacology; D001597:Benzylidene Compounds / Q000494:pharmacology; D045744:Cell Line, Tumor / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002599:Chalcone / Q000031:analogs & derivatives / Q000494:pharmacology; D004354:Drug Screening Assays, Antitumor / Q000379:methods*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D063990:Gene Ontology; D006801:Humans; D058990:Molecular Targeted Therapy; D015398:Signal Transduction; D054852:Small Molecule Libraries / Q000494:pharmacology*; D064726:Triple Negative Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism
chemical_list: C545429:2-(3,4-dihydroxybenzylidene)-5-methoxybenzofuran-3(2H)-one; C000598973:3-(3,4-dihydroxybenzylidene)benzofuran-2(3H)-one; D000970:Antineoplastic Agents; D001572:Benzofurans; D001597:Benzylidene Compounds; D054852:Small Molecule Libraries; D002599:Chalcone