Hypoxia inducible factor 1α gene (HIF-1α) splice variants: potential prognostic biomarkers in breast cancer

<p>Abstract</p> <p>Background</p> <p>Hypoxia-inducible factor 1 (HIF-1) is a master transcriptional regulator of genes regulating oxygen homeostasis. The HIF-1 protein is composed of two HIF-1α and HIF-1β/aryl hydrocarbon receptor nuclear translocator (ARNT) subunits. The prognostic relevance of HIF-1α protein overexpression has been shown in breast cancer. The impact of HIF-1α alternative splice variant expression on breast cancer prognosis in terms of metastasis risk is not well known.</p> <p>Methods</p> <p>Using real-time quantitative reverse transcription PCR assays, we measured mRNA concentrations of total <it>HIF-1α </it>and 4 variants in breast tissue specimens in a series of 29 normal tissues or benign lesions (normal/benign) and 53 primary carcinomas. In breast cancers <it>HIF-1α </it>splice variant levels were compared to clinicopathological parameters including tumour microvessel density and metastasis-free survival.</p> <p>Results</p> <p><it>HIF-1α </it>isoforms containing a three base pairs TAG insertion between exon 1 and exon 2 (designated <it>HIF-1α</it>^<it>TAG</it>) and <it>HIF-1α</it>^{<it>736 </it>}mRNAs were found expressed at higher levels in oestrogen receptor (OR)-negative carcinomas compared to normal/benign tissues (<it>P </it>= 0.009 and <it>P </it>= 0.004 respectively). In breast carcinoma specimens, lymph node status was significantly associated with <it>HIF-1α</it>^{<it>TAG </it>}mRNA levels (<it>P </it>= 0.037). Significant statistical association was found between tumour grade and <it>HIF-1α</it>^{<it>TAG </it>}(<it>P </it>= 0.048), and total <it>HIF-1α </it>(<it>P </it>= 0.048) mRNA levels. <it>HIF-1α</it>^{<it>TAG </it>}mRNA levels were also inversely correlated with both oestrogen and progesterone receptor status (<it>P </it>= 0.005 and <it>P </it>= 0.033 respectively). Univariate analysis showed that high <it>HIF-1α</it>^{<it>TAG </it>}mRNA levels correlated with shortened metastasis free survival (<it>P </it>= 0.01).</p> <p>Conclusions</p> <p>Our results show for the first time that mRNA expression of a <it>HIF-1α</it>^{<it>TAG </it>}splice variant reflects a stage of breast cancer progression and is associated with a worse prognosis.</p> <p>See commentary: <url>http://www.biomedcentral.com/1741-7015/8/45</url></p