Abstract
IntroductionThe 19q12 locus is amplified in a subgroup of oestrogen receptor (ER)-negative grade III breast cancers. This amplicon comprises nine genes, including cyclin E1 (CCNE1), which has been proposed as its 'driver'. The aim of this study was to identify the genes within the 19q12 amplicon whose expression is required for the survival of cancer cells harbouring their amplification.MethodsWe investigated the presence of 19q12 amplification in a series of 313 frozen primary breast cancers and 56 breast cancer cell lines using microarray comparative genomic hybridisation (aCGH). The nine genes mapping to the smallest region of amplification on 19q12 were silenced using RNA interference in phenotypically matched breast cancer cell lines with (MDA-MB-157 and HCC1569) and without (Hs578T, MCF7, MDA-MB-231, ZR75.1, JIMT1 and BT474) amplification of this locus. Genes whose silencing was selectively lethal in amplified cells were taken forward for further validation. The effects of cyclin-dependent kinase 2 (CDK2) silencing and chemical inhibition were tested in cancer cells with and without CCNE1 amplification.Results19q12 amplification was identified in 7.8% of ER-negative grade III breast cancer. Of the nine genes mapping to this amplicon, UQCRFS1, POP4, PLEKHF1, C19ORF12, CCNE1 and C19ORF2 were significantly over-expressed when amplified in primary breast cancers and/or breast cancer cell lines. Silencing of POP4, PLEKHF1, CCNE1 and TSZH3 selectively reduced cell viability in cancer cells harbouring their amplification. Cancer cells with CCNE1 amplification were shown to be dependent on CDK2 expression and kinase activity for their survival.ConclusionsThe 19q12 amplicon may harbour more than a single 'driver', given that expression of POP4, PLEKHF1, CCNE1 and TSZH3 is required for the survival of cancer cells displaying their amplification. The observation that cancer cells harbouring CCNE1 gene amplification are sensitive to CDK2 inhibitors provides a rationale for the testing of these chemical inhibitors in a subgroup of patients with ER-negative grade III breast cancers.
Highlights
The 19q12 locus is amplified in a subgroup of oestrogen receptor (ER)-negative grade III breast cancers
The aims of this study were (i) to characterise the 19q12 amplicon in breast cancer, (ii) to determine the genes that are overexpressed when amplified in this amplicon, (iii) to investigate which of the genes mapping to this amplicon are selectively required for the survival of cells harbouring their amplification, and (iv) to determine if cancer cells with cyclin E1 (CCNE1) gene amplification are dependent on CCNE1 cell cycle-related functions for their survival
Tumours were classified into ER-positive/HER2-negative, ER-negative/HER2-negative and HER2-positive subgroups, given i) the results of recent studies demonstrating that the transcriptomic profiles of ER-positive/HER2-negative, ER-negative/HER2-negative and HER2-positive tumours are fundamentally different [34,35], ii) the technical issues related to the assignment of tumour profiled with different platforms into the ‘intrinsic’ molecular subtypes [36,37], and iii) that these subgroups are currently employed to define the systemic therapy for patients with breast cancer
Summary
The 19q12 locus is amplified in a subgroup of oestrogen receptor (ER)-negative grade III breast cancers. Using a combination of microarray-based comparative genomic hybridisation (aCGH) and gene expression profiling [11,12,13,14,15,16,17,18,19], previous studies have identified genes which are consistently overexpressed when amplified and suggested potential “amplicon drivers” (for example, FGFR1, FGFR2, GAB2, PPAPDC1B and ZNF703). It should be noted, that whilst many potential targets have been postulated, critical molecular drivers of several amplicons remain elusive
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