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.

Abstract

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.

• Authors: Peter Chan, Andreas Möller, Mira C P Liu, Jaclyn E Sceneay, Christina S F Wong, Nic Waddell, Katie T Huang, Alexander Dobrovic, Ewan K A Millar, Sandra A O'Toole, Catriona M McNeil, Robert L Sutherland, David D Bowtell, Stephen B Fox
• Journal: Breast cancer research : BCR (Breast Cancer Res) Vol. 13 Issue 1 Pg. R19 (Feb 09 2011) ISSN: 1465-542X [Electronic] England
• PMID: 21306611 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Nuclear Proteins
• Tumor Suppressor Protein p53
• Ubiquitin-Protein Ligases
• seven in absentia proteins

Topics

• Adult
• Aged
• Aged, 80 and over
• Breast Neoplasms (genetics, mortality, pathology)
• Cohort Studies
• DNA Methylation
• Female
• Gene Dosage
• Gene Expression
• Humans
• Kaplan-Meier Estimate
• Mammary Glands, Human (metabolism)
• Middle Aged
• Neoplasm Staging
• Nuclear Proteins (genetics, metabolism)
• Phenotype
• Promoter Regions, Genetic
• Tumor Suppressor Protein p53 (metabolism)
• Ubiquitin-Protein Ligases (genetics, metabolism)
• Young Adult