SIAH2 plays a significant role in the hypoxic response by regulating the abundance of HIF-1alpha, 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.

Immunohistochemical evaluation of SIAH2 protein expression was conducted in normal breast tissues and in tissue microarrays comprising ductal carcinoma in situ and a cohort of invasive breast carcinomas. Correlation analysis was performed between SIAH2 and clinicopathological variables and intrinsic breast cancer subgroups and validated on a cohort of 293 invasive ductal carcinomas. Promoter methylation, gene copy number and mRNA expression of SIAH2 was determined in a panel of basal-like tumors and cell lines.

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 ER and PR and a positive association with tumor grade, HER2, p53 and intrinsic basal-like subtype. A logistic regression confirmed the significant positive association between SIAH2 expression and 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 a univariate but not multivariate analysis.

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.

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