ZNF703 is a common Luminal B breast cancer oncogene that differentially regulates luminal and basal progenitors in human mammary epithelium

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PROBLEM:

Despite their better overall prognosis, the survival rates of patients with ER‐positive breast cancers are extremely variable and identifying biomarkers and drivers of poor outcome is an important step to improve clinical management. Luminal B breast cancers are the clinically more aggressive ER‐positive tumours and characterizing the genomic drivers (oncogenes) at chromosomal loci frequently altered in this subtype has been the subject of intense research.

RESULTS:

Here, we characterize ZNF703 as the driver of the frequent amplification of a distal 8p12 locus, which occurs in around 1/3 of Luminal B breast cancers, less frequently in other ER‐positive tumours and uncommonly in ER‐negative tumours. ZNF703 behaves as a classical oncogene in that it transforms non‐malignant cells and increases cellular proliferation. The amplification of the gene is accompanied by overexpression of the encoded protein, which can be observed using immunostaining of tissue sections, making its detection in routine histopathology laboratories possible.

IMPACT:

ZNF703 is a new breast cancer oncogene and a potential prognostic biomarker and therapeutic target in the more aggressive ER‐positive breast cancers.

INTRODUCTION

In human cancers, genes altered by amplification and concomitant overexpression are considered candidate oncogenes (Santarius et al, 2010). However, amplicons often include several candidates making it difficult to delineate the true cancer gene. Amplification (frequently high‐level) of the proximal chromosomal arm 8p (8p12) is common in breast cancer (Chin et al, 2006). There are four amplification cores consistently identified at 8p12 with the most telomeric of these cores being the most common and characterized originally by our group as containing only 6 genes (Garcia et al, 2005), a finding consistently confirmed by other studies (Adelaide et al, 2007; Gelsi‐Boyer et al, 2005; Haverty et al, 2008; Kwek et al, 2009; Prentice et al, 2005). Correlation between copy number and gene expression was previously used to exclude GPR124, leaving as candidates the following five genes, ordered from telomere to centromere: ZNF703, ERLIN2, PROSC, BRF2, and RAB11FIP1 (Adelaide et al, 2007; Garcia et al, 2005; Gelsi‐Boyer et al, 2005; Haverty et al, 2008; Kwek et al, 2009). Despite this work, the identity of the driver oncogene at the most telomeric amplicon at...