FGFR1 emerges as a potential therapeutic target for lobular breast carcinomas.

Abstract

PURPOSE 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. EXPERIMENTAL DESIGN 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.

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@article{ReisFilho2006FGFR1EA, title={FGFR1 emerges as a potential therapeutic target for lobular breast carcinomas.}, author={Jorge S Reis-Filho and Pete T. Simpson and Nicholas C. Turner and Maryou Ballo Lambros and Chris Jones and Alan Mackay and Anita Grigoriadis and David Sarri{\'o} and Kay Savage and Tim J. Dexter and Marjan Iravani and Kerry Fenwick and Barbara L. Weber and David Hardisson and Fernando Schmitt and Jos{\'e} Palacios and Sunil R Lakhani and Alan Ashworth}, journal={Clinical cancer research : an official journal of the American Association for Cancer Research}, year={2006}, volume={12 22}, pages={6652-62} }