Research article
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
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* Corresponding authors: Andreas Möller andreas.moeller@petermac.org - Stephen B Fox stephen.fox@petermac.org
- † Equal contributors
1 Department of Pathology, Peter MacCallum Cancer Centre, Locked Bag 1 A'Beckett Street, Melbourne, Victoria 8006, Australia
2 Research Division, Cancer Genetics and Genomics, Peter MacCallum Cancer Centre, Locked Bag 1 A'Beckett Street, Melbourne, Victoria 8006, Australia
3 Department of Pathology, University of Melbourne, Royal Parade, Parkville, Victoria 3010, Australia
4 Queensland Centre for Medical Genomics, Institute for Molecular Bioscience, University of Queensland, Brisbane, Queensland 4072, Australia
5 Cancer Research Program, Garvan Institute of Medical Research, 384 Victoria Street, Darlinghurst, NSW 2010, Australia
6 South East Area Laboratory Services, St George Hospital, Kogarah, NSW 2217, Australia
7 School of Medicine, University of Western Sydney, Campbelltown NSW 2751, Australia
8 School of Medical Sciences, Faculty of Medicine, University of New South Wales, Sydney, NSW 2052, Australia
9 Department of Tissue Pathology and Diagnostic Oncology, Royal Prince Alfred Hospital, Camperdown, NSW 2006, Australia
10 Faculty of Medicine, University of Sydney, NSW 2006, Australia
11 Department of Medical Oncology & Breast Cancer Institute of New South Wales, University of Sydney, Westmead Hospital, Westmead, NSW 2145, Australia
12 Western Clinical School, University of Sydney, Westmead Hospital, Westmead, NSW 2145, Australia
Breast Cancer Research 2011, 13:R19 doi:10.1186/bcr2828
Published: 9 February 2011Abstract
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-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.
Methods
Immunohistochemical 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.
Results
There 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.
Conclusions
SIAH2 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.