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.

A high-resolution integrated analysis of genetic and expression profiles of breast cancer cell lines

“…We [31,42,55] and others [39,43] have previously demonstrated that genes significantly overexpressed when amplified are likely amplicon drivers, as the expression of these genes is required for the survival of cells harbouring amplification of their genomic region. Our integrated analysis has not only identified genes previously shown to be potential drivers of amplicons 8p11.2 (FGFR1), 8q24 (MYC), 11q13 (CTTN, FADD), 17q12 (ERBB2) and 20q13 (AURKA), but also identified a list of 269 that should be investigated as potential therapeutic targets in the amplicons on chromosomes 1q, 3q, 6p, 8q, 13q, 14q, 17q, 19q and 20q (Table 4; Supplementary Table S6).…”

“…Previous studies have demonstrated that expression of genes consistently overexpressed when amplified may be required for the survival of cells harbouring amplification of their genetic loci [31,39,42,43]. To identify the likeliest drivers of the amplicons 8p11.2-p12, 8q24, 11q13.3, 17q12-q21 and 20q13.3, we first retrieved the genes mapping to these amplicons, performed a Pearson's correlation to determine those whose expression correlate with copy number and then identified all genes that were overexpressed when amplified within each region using a Wilcoxon sign rank test (Fig.…”

Comprehensive genetic and functional characterization of IPH‐926: a novel CDH1‐null tumour cell line from human lobular breast cancer

“…8p12-p11 and 11q12-q13, loss of 11q14-qter, gain of 12q23-q24, loss of 15q21, loss of 16q22, gain of 19p13, gain of 20q11-q13, and several other distinct alterations [9,10]. The total number of chromosomal arms with genomic imbalances in primary ILBC ranges from 3 to 15 [10].…”

“…Profiling approaches focusing on genomic imbalances established that nearly all ILBCs harbour a loss of 16q22, the locus of CDH1 [9]. This alteration is frequently accompanied A CDH1-null cell line from lobular breast cancer 621 by gain of 1q, loss of 8p23-p22, concomitant gains of 8p12-p11 and 11q12-q13, and loss of 11q14-qter [9,10]. In the clinics, ILBCs frequently metastasize to the peritoneum and abdominal organs [11].…”

“…Furthermore, HCC-2185 and MDA-MB-330 were not tumourigenic in vivo [18,19]. Recently, it was proposed that the cell line MDA-MB-134 might be derived from an ILBC [10]. However, MDA-MB-134 was originally reported to be derived from a ductal mammary carcinoma [21] is widely perceived as a ductal breast cancer cell line [e.g., 15], usually non-tumourigenic in vivo [15,18,[21][22][23] and lacking E-cadherin expression due to a homozygous mutation of the CDH1 gene [24].…”