Hypoxia inducible factor-1α (HIF-1α) and matrix metalloproteinase 9 (MMP-9) expression in invasive breast cancer.

Hypoxia inducible factor-1α (HIF-1α) and matrix metalloproteinase 9 (MMP-9) expression in invasive breast cancer.

Anastasios D Papanastasiou, Haralabos Papatheodorou, Natassa Alexandrou, Foteini Zafeiropoulou, Michalis Leotsinidis, Maria Repanti, Helen Papadaki


Aim: Hypoxia has a key role in cancer progression and metastasis. Low tissue oxygen availability induces the activity of HIFs (Hypoxia-Inducible Factors) to up-regulate a panel of invasion related genes, in a plethora of solid tumors. MMPs (matrix metalloproteinases) are enzymes produced from normal and cancerous cells with the ability to degrade extracellular stroma, priming invasion. The aim of this study was to identify possible gene and protein associations between HIF-1α and MMP-9 in invasive breast cancer.

Materials and Methods: A total of 96 FFPE (Formalin-Fixed Paraffin-Embedded) breast cancer samples were evaluated for HIF-1α and MMP-9 protein expression. Publicly available gene expression datasets for breast cancer were analyzed for HIF-1a and MMP-9 gene expression. Results were correlated with clinicopathological parameters and patient clinical outcome.

Results: MMP-9 and HIF-1α showed a positive correlation both at the mRNA (p<0.001) and protein (p=0.01) expression levels, in samples from breast cancer patients. This correlation was specific because HIF-2b, another member of the HIF family, presented with a negative correlation with MMP-9 gene expression. Furthermore, mRNA and protein expression of MMP-9 had a negative correlation (p<0.01) with relapse-free survival (RFS) and a positive correlation (p<0.01) with lymph node status (N1), respectively. In addition, patients with high mRNA expression of HIF-1α had significantly (p<0.001) shorter OS and RFS than did patients with low levels of HIF-1a.

Conclusions: HIF-1α and MMP-9 co-expression may represent a novel marker of worse clinical outcome in breast cancer patients, predicting increased metastatic capacity of cancer cells.


Breast Ca, HIF1-alpha, MMP-9

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