Hypoxia inducible factor 1alpha gene (HIF-1alpha) splice variants: potential prognostic biomarkers in breast cancer.
BACKGROUND
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-1alpha and HIF-1beta/aryl hydrocarbon receptor nuclear translocator (ARNT) subunits. The prognostic relevance of HIF-1alpha protein overexpression has been shown in breast cancer. The impact of HIF-1alpha alternative splice variant expression on breast cancer prognosis in terms of metastasis risk is not well known.


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


RESULTS
HIF-1alpha isoforms containing a three base pairs TAG insertion between exon 1 and exon 2 (designated HIF-1alphaTAG) and HIF-1alpha736 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-1alphaTAG mRNA levels (P = 0.037). Significant statistical association was found between tumour grade and HIF-1alphaTAG (P = 0.048), and total HIF-1alpha (P = 0.048) mRNA levels. HIF-1alphaTAG 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-1alphaTAG mRNA levels correlated with shortened metastasis free survival (P = 0.01).


CONCLUSIONS
Our results show for the first time that mRNA expression of a HIF-1alphaTAG splice variant reflects a stage of breast cancer progression and is associated with a worse prognosis.See commentary: http://www.biomedcentral.com/1741-7015/8/45.
Dales
Jean-Philippe
JP
Plateforme Transcriptome, CRO2, Marseille, France. Jdales@ap-hm.fr
Beaufils
Nathalie
N
Silvy
Monique
M
Picard
Christophe
C
Pauly
Vanessa
V
Pradel
Vincent
V
Formisano-Tréziny
Christine
C
Bonnier
Pascal
P
Giusiano
Sophie
S
Charpin
Colette
C
Gabert
Jean
J
D000293:Adolescent; D000328:Adult; D000368:Aged; D015415:Biomarkers; D001943:Breast Neoplasms / Q000175:diagnosis* / Q000556:secondary*; D002648:Child; D005260:Female; D020869:Gene Expression Profiling; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000032:analysis* / Q000235:genetics*; D008875:Middle Aged; D009362:Neoplasm Metastasis / Q000175:diagnosis*; D011379:Prognosis; D020033:Protein Isoforms / Q000032:analysis* / Q000235:genetics*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D055815:Young Adult
D015415:Biomarkers; C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D020033:Protein Isoforms