title: FGFR1 emerges as a potential therapeutic target for lobular breast carcinomas.
abstract: OBJECTIVE
  Classic lobular carcinomas (CLC) account for 10% to 15% of all breast cancers. At the genetic level, CLCs show recurrent physical loss of chromosome16q coupled with the lack of E-cadherin (CDH1 gene) expression. However, little is known about the putative therapeutic targets for these tumors. The aim of this study was to characterize CLCs at the molecular genetic level and identify putative therapeutic targets.
  
  
  METHODS
  We subjected 13 cases of CLC to a comprehensive molecular analysis including immunohistochemistry for E-cadherin, estrogen and progesterone receptors, HER2/neu and p53; high-resolution comparative genomic hybridization (HR-CGH); microarray-based CGH (aCGH); and fluorescent and chromogenic in situ hybridization for CCND1 and FGFR1.
  
  
  RESULTS
  All cases lacked the expression of E-cadherin, p53, and HER2, and all but one case was positive for estrogen receptors. HR-CGH revealed recurrent gains on 1q and losses on 16q (both, 85%). aCGH showed a good agreement with but higher resolution and sensitivity than HR-CGH. Recurrent, high level gains at 11q13 (CCND1) and 8p12-p11.2 were identified in seven and six cases, respectively, and were validated with in situ hybridization. Examination of aCGH and the gene expression profile data of the cell lines, MDA-MB-134 and ZR-75-1, which harbor distinct gains of 8p12-p11.2, identified FGFR1 as a putative amplicon driver of 8p12-p11.2 amplification in MDA-MB-134. Inhibition of FGFR1 expression using small interfering RNA or a small-molecule chemical inhibitor showed that FGFR1 signaling contributes to the survival of MDA-MB-134 cells.
  
  
  CONCLUSIONS
  Our findings suggest that receptor FGFR1 inhibitors may be useful as therapeutics in a subset of CLCs.
authors.affiliation: The Breakthrough Breast Cancer Research Centre, Institute of Cancer Research, London, United Kingdom. jorgerf@icr.ac.uk
authors.forename: Jorge Sergio
authors.initials: JS
authors.lastname: Reis-Filho
authors.forename: Pete T
authors.initials: PT
authors.lastname: Simpson
authors.forename: Nicholas C
authors.initials: NC
authors.lastname: Turner
authors.forename: Maryou Ballo
authors.initials: MB
authors.lastname: Lambros
authors.forename: Chris
authors.initials: C
authors.lastname: Jones
authors.forename: Alan
authors.initials: A
authors.lastname: Mackay
authors.forename: Anita
authors.initials: A
authors.lastname: Grigoriadis
authors.forename: David
authors.initials: D
authors.lastname: Sarrio
authors.forename: Kay
authors.initials: K
authors.lastname: Savage
authors.forename: Tim
authors.initials: T
authors.lastname: Dexter
authors.forename: Marjan
authors.initials: M
authors.lastname: Iravani
authors.forename: Kerry
authors.initials: K
authors.lastname: Fenwick
authors.forename: Barbara
authors.initials: B
authors.lastname: Weber
authors.forename: David
authors.initials: D
authors.lastname: Hardisson
authors.forename: Fernando Carlos
authors.initials: FC
authors.lastname: Schmitt
authors.forename: Jose
authors.initials: J
authors.lastname: Palacios
authors.forename: Sunil R
authors.initials: SR
authors.lastname: Lakhani
authors.forename: Alan
authors.initials: A
authors.lastname: Ashworth
mesh_terms: D014408:Biomarkers, Tumor / Q000032:analysis; D001943:Breast Neoplasms / Q000235:genetics* / Q000378:metabolism; D015820:Cadherins / Q000378:metabolism; D018275:Carcinoma, Lobular / Q000235:genetics* / Q000378:metabolism; D045744:Cell Line, Tumor; D002470:Cell Survival; D002869:Chromosome Aberrations; D002880:Chromosomes, Human, Pair 11; D002898:Chromosomes, Human, Pair 8; D015536:Down-Regulation; D044127:Epigenesis, Genetic; D005784:Gene Amplification; D015972:Gene Expression Regulation, Neoplastic; D018740:Genetic Heterogeneity; D006801:Humans; D007150:Immunohistochemistry / Q000379:methods; D009693:Nucleic Acid Hybridization / Q000379:methods; D020411:Oligonucleotide Array Sequence Analysis / Q000379:methods; D051496:Receptor, Fibroblast Growth Factor, Type 1 / Q000235:genetics* / Q000502:physiology*; D014407:Tumor Cells, Cultured
chemical_list: D014408:Biomarkers, Tumor; D015820:Cadherins; D051496:Receptor, Fibroblast Growth Factor, Type 1