Email updates

Keep up to date with the latest news and content from BMC Medicine and BioMed Central.

Journal App

google play app store
Open Access Research article

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

Jean-Philippe Dales12*, Nathalie Beaufils3, Monique Silvy4, Christophe Picard4, Vanessa Pauly5, Vincent Pradel5, Christine Formisano-Tréziny1, Pascal Bonnier6, Sophie Giusiano2, Colette Charpin2 and Jean Gabert13

  • * Corresponding author: Jean-Philippe Dales

  • † Equal contributors

Author Affiliations

1 Plateforme Transcriptome, CRO2, Marseille, France

2 Department of Pathology, Hôpital Nord, Marseille, France

3 Biochemistry and Molecular Biology, Hôpital Nord, Marseille, France

4 Etablissement Français du Sang Alpes Méditerranée, Marseille, France

5 Department of Medical Information, Hôpital Sainte Marguerite, Marseille, France

6 Department of Gynaecologic Oncology, Hôpital de la Conception, Assistance-Publique Hôpitaux de Marseille, Université de la Méditerranée, Marseille, France

For all author emails, please log on.

BMC Medicine 2010, 8:44  doi:10.1186/1741-7015-8-44

Published: 12 July 2010



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.


Using real-time quantitative reverse transcription PCR assays, we measured mRNA concentrations of total HIF-1α 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 HIF-1α splice variant levels were compared to clinicopathological parameters including tumour microvessel density and metastasis-free survival.


HIF-1α isoforms containing a three base pairs TAG insertion between exon 1 and exon 2 (designated HIF-1αTAG) and HIF-1α736 mRNAs were found expressed at higher levels in oestrogen receptor (OR)-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-1αTAG mRNA levels (P = 0.037). Significant statistical association was found between tumour grade and HIF-1αTAG (P = 0.048), and total HIF-1α (P = 0.048) mRNA levels. HIF-1αTAG mRNA levels were also inversely correlated with both oestrogen and progesterone receptor status (P = 0.005 and P = 0.033 respectively). Univariate analysis showed that high HIF-1αTAG mRNA levels correlated with shortened metastasis free survival (P = 0.01).


Our results show for the first time that mRNA expression of a HIF-1αTAG splice variant reflects a stage of breast cancer progression and is associated with a worse prognosis.

See commentary: webcite