High‐resolution genomic analysis of the 11q13 amplicon in breast cancers identifies synergy with 8p12 amplification, involving the mTOR targets S6K2 and 4EBP1

Abstract

The chromosomal region 11q13 is amplified in 15-20% of breast cancers; an event associated with oestrogen receptor (ER) expression but also implicated in resistance to endocrine therapy. Coamplifications of the 11q13 and 8p12 regions are common, suggesting synergy between the amplicons. The aim was to identify candidate oncogenes in the 11q13 region based on recurrent amplification patterns and correlations to mRNA expression levels.Furthermore, the 11q13/8p12 coamplification and its prognostic value, was evaluated at the DNA and the mRNA levels. Affymetrix 250K NspI arrays were used for whole genome screening of DNA copy number changes in 29 breast tumours. To identify amplicon cores at 11q13 and 8p12, Genomic Identification of Significant Targets in Cancer (GISTIC) was applied. The mRNA expression levels of candidate oncogenes in the amplicons (RAD9A, RPS6KB2 (S6K2), CCND1, FGF19, FGF4, FGF3, PAK1, GAB2 (11q13); EIF4EBP1(4EBP1), PPAPDC1B and FGFR1 (8p12)) were evaluated using real-time PCR. Resulting data revealed three main amplification cores at 11q13. ER expression was associated with the central 11q13 amplification core, encompassing CCND1, whereas 8p12 amplification/gene expression correlated to S6K2 in a proximal 11q13 core. Amplification of 8p12 and high expression of 4EBP1 or FGFR1 was associated with a poor outcome in the group. In conclusion, SNP arrays have enabled mapping of the 11q13 amplicon in breast tumours with high resolution. A proximal 11q13 core including S6K2 was identified as involved in the coamplification/coexpression with 8p12, suggesting synergy between the mTOR targets S6K2 and 4EBP1 in breast cancer development and progression.3

The ins and outs of fibroblast growth factor receptor signalling

“…Whether overexpression of these ligands alone can drive tumorigenesis is yet to be elucidated, although aberrant receptor expression may also be implicated [30]. Chromosomal region 8p12, which encodes FGFR1, is frequently amplified in breast cancer and co-amplification with 11q13 (region for FGF2, FGF4 and FGF19) is associated with a poor patient outcome [31]. Further evidence for FGFR signalling in breast cancer development has come from recent genome wide association studies identifying SNPs (single nucleotide polymorphisms) in the second intron of the FGFR2 gene.…”

Loss of protein tyrosine phosphatase, non-receptor type 2 is associated with activation of AKT and tamoxifen resistance in breast cancer

“…Deletions at 18p were estimated in 25 of the samples using Affymetrix SNP Gene Copy number arrays as previously described [14].…”

4E-BP1, a multifactor regulated multifunctional protein

“…Gene amplification and the resultant high expression of 4E-BP1 were shown to indicate a poor prognosis. 40,41 Another suggested mechanism is through transcription. High 4E-BP1 mRNA, independent of phosphorylation status, was associated with an adverse outcome in breast cancer, especially in ER-positive subgroup.…”