The expression of the ubiquitin ligase SIAH2 (seven in absentia homolog 2) is mediated through gene copy number in breast cancer and is associated with a basal-like phenotype and p53 expression

Peter Chan,Sandra A O'Toole,Christina Sf Wong,Robert L Sutherland,Jaclyn E Sceneay,Andreas Möller,Ewan Ka Millar,Katie T Huang,Nic Waddell,Catriona M Mcneil,Mira Cp Liu,David D Bowtell,Stephen B Fox,Alexander Dobrovic

doi:10.1186/bcr2828

Abstract

IntroductionThe seven in absentia homolog 2 (SIAH2) protein plays a significant role in the hypoxic response by regulating the abundance of hypoxia-inducible factor-α; however, its role in breast carcinoma is unclear. We investigated the frequency and expression pattern of SIAH2 in two independent cohorts of sporadic breast cancers.MethodsImmunohistochemical evaluation of SIAH2protein expression was conducted in normal breast tissues and in tissue microarrays comprising ductal carcinoma in situ (DCIS) and a cohort of invasive breast carcinomas. Correlation analysis was performed between SIAH2 and clinicopathological variables and intrinsic breast cancer subgroups and validated in a cohort of 293 invasive ductal carcinomas. Promoter methylation, gene copy number and mRNA expression of SIAH2 were determined in a panel of basal-like tumors and cell lines.ResultsThere was a significant increase in nuclear SIAH2 expression from normal breast tissues through to DCIS and progression to invasive cancers. A significant inverse correlation was apparent between SIAH2 and estrogen receptor and progesterone receptor and a positive association with tumor grade, HER2, p53 and an intrinsic basal-like subtype. Logistic regression analysis confirmed the significant positive association between SIAH2 expression and the basal-like phenotype. No SIAH2 promoter methylation was identified, yet there was a significant correlation between SIAH2 mRNA and gene copy number. SIAH2-positive tumors were associated with a shorter relapse-free survival in univariate but not multivariate analysis.ConclusionsSIAH2 expression is upregulated in basal-like breast cancers via copy number changes and/or transcriptional activation by p53 and is likely to be partly responsible for the enhanced hypoxic drive through abrogation of the prolyl hydroxylases.

Highlights

The seven in absentia homolog 2 (SIAH2) protein plays a significant role in the hypoxic response by regulating the abundance of hypoxia-inducible factor-a; its role in breast carcinoma is unclear
SIAH2 expression in normal breast, in situ and invasive breast carcinomas SIAH2 expression was identified in the nuclei of occasional cells within the luminal layer of ducts and acini in normal breast tissues in three of 10 patients (30%)
This expression was usually of mild to moderate intensity, and when stratified using the cutoff used for the tumors, all were considered negative for SIAH2 (Figure 1A)

Summary

Introduction

The seven in absentia homolog 2 (SIAH2) protein plays a significant role in the hypoxic response by regulating the abundance of hypoxia-inducible factor-a; its role in breast carcinoma is unclear. Under hypoxia, the prolyl hydroxylases have limited molecular oxygen and are less effective, which enables HIF-1a stabilization, translocation to the nucleus and initiation of gene transcription that benefits the tumor. Siah proteins are involved in hypoxia signaling via regulation of HIF-1a [3] through the targeted degradation of prolyl hydroxylases under hypoxic conditions. SIAH2-knockout mice have a delayed and abrogated response to hypoxic conditions that is mediated through reduced levels of HIF-1a [3,4]. These data suggest that Siah proteins may significantly alter HIF signaling through modulation of the prolyl hydroxylases

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