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An In Vitro Dormancy Model of Estrogen-sensitive Breast Cancer in the Bone Marrow: A Tool for Molecular Mechanism Studies and Hypothesis Generation
Published on: June 30, 2015
FGFR1 emerges as a potential therapeutic target for lobular breast carcinomas
Jorge Sergio Reis-Filho1, Pete T Simpson, Nicholas C Turner
1The Breakthrough Breast Cancer Research Centre, Institute of Cancer Research, London, United Kingdom. jorgerf@icr.ac.uk
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.
Insights
Classic lobular breast carcinomas (CLC) often lack E-cadherin. This study identified FGFR1 amplification in CLCs, suggesting FGFR1 inhibitors as potential targeted therapies for this breast cancer subtype.
Area of Science:
- Oncology
- Genetics
- Molecular Biology
Background:
- Classic lobular carcinomas (CLC) represent 10-15% of breast cancers.
- CLCs are characterized by chromosome 16q loss and absent E-cadherin expression.
- Therapeutic targets for CLCs remain largely undefined.
Purpose of the Study:
- To molecularly characterize CLCs.
- To identify potential therapeutic targets for CLCs.
Main Methods:
- Comprehensive molecular analysis of 13 CLC cases.
- Techniques included immunohistochemistry, high-resolution comparative genomic hybridization (HR-CGH), and microarray-based CGH (aCGH).
- In situ hybridization was used to validate gene amplifications.
Main Results:
- Consistent E-cadherin loss and frequent 16q deletions were observed.
- Recurrent high-level gains at 11q13 (CCND1) and 8p12-p11.2 were identified.
- FGFR1 was identified as a driver of 8p12-p11.2 amplification, and its inhibition impaired MDA-MB-134 cell survival.
Conclusions:
- FGFR1 amplification is a key event in a subset of CLCs.
- FGFR1 inhibitors show promise as targeted therapeutics for CLCs.
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