Abstract LB-215: Hypoxia inducible factor-1 alpha (HIF-1α) splice variants: Potential prognostic biomarkers in breast cancer

Abstract

Abstract Background: Hypoxia-inducible factor-1 (HIF-1) is a master transcriptional regulator of genes regulating oxygen homeostasis. HIF-1 protein is composed of two HIF-1α and HIF-1ß/ARNT subunits. Prognostic relevance of HIF-1α protein overexpression has been shown in breast cancer. The impact of HIF-1α alternative splice variants expression on breast cancer prognosis in term of metastasis risk is not well known. Methods: With real-time quantitative reverse transcription PCR assays, we measured mRNA concentrations of total HIF-1α and four variants in breast specimens of a series of 29 normal tissues or benign lesions (normal/benign) and 53 primary carcinomas. In breast cancers HIF-1α splice variant levels were compared to clinicopathological parameters including tumor microvessel density and metastasis-free survival. Results: HIF-1α isoforms containing three base pairs TAG insertion between exon 1 and exon 2 (designated HIF-1 TAG) and HIF-1 736mRNAs were found expressed at higher levels in estrogen receptor negative carcinomas compared to normal/benign tissues (p=0.009 and p=0.004 respectively). In breast carcinoma specimens, lymph node status was significantly associated with HIF-1 TAG mRNA levels (p=0.037). Significant statistical association was found between tumor grade and HIF-1 TAG (p=0.048), and total HIF-1 (p=0.048) mRNA levels. HIF-1 TAGmRNA levels also correlated inversely with both estrogen and progesterone receptor status (p=0.005 and p=0.033 respectively). Univariate analysis showed that high HIF-1 TAG mRNA levels correlated with shortened metastasis free survival (p=0.01). Conclusion: Our results show for the first time that mRNA expression of HIF-1 TAG splice variant reflects a stage of breast cancer progression and is associated with a worse prognosis. Note: This abstract was not presented at the AACR 101st Annual Meeting 2010 because the presenter was unable to attend. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr LB-215.