Abstract
BackgroundTumour hypoxia is a driver of breast cancer progression associated with worse prognosis and more aggressive disease. The cellular response to hypoxia is mediated by the hypoxia-inducible transcription factors HIF-1 and HIF-2, whose transcriptional activity is canonically regulated through their oxygen-labile HIF-α subunits. These are constitutively degraded in the presence of oxygen; however, HIF-1α can be stabilised, even at high oxygen concentrations, through the activation of HER receptor signalling. Despite this, there is still limited understanding on how HER receptor signalling interacts with HIF activity to contribute to breast cancer progression in the context of tumour hypoxia.Methods2D and 3D cell line models were used alongside microarray gene expression analysis and meta-analysis of publicly available gene expression datasets to assess the impact of HER2 overexpression on HIF-1α/HIF-2α regulation and to compare the global transcriptomic response to acute and chronic hypoxia in an isogenic cell line model of HER2 overexpression.ResultsHER2 overexpression in MCF7 cells leads to an increase in HIF-2α but not HIF-1α expression in normoxia and an increased upregulation of HIF-2α in hypoxia. Global gene expression analysis showed that HER2 overexpression in these cells promotes an exaggerated transcriptional response to both short-term and long-term hypoxia, with increased expression of numerous hypoxia response genes. HIF-2α expression is frequently higher in HER2-overexpressing tumours and is associated with worse disease-specific survival in HER2-positive breast cancer patients. HER2-overexpressing cell lines demonstrate an increased sensitivity to targeted HIF-2α inhibition through either siRNA or the use of a small molecule inhibitor of HIF-2α translation.ConclusionsThis study suggests an important interplay between HER2 expression and HIF-2α in breast cancer and highlights the potential for HER2 to drive the expression of numerous hypoxia response genes in normoxia and hypoxia. Overall, these findings show the importance of understanding the regulation of HIF activity in a variety of breast cancer subtypes and points to the potential of targeting HIF-2α as a therapy for HER2-positive breast cancer.
Highlights
Tumour hypoxia is a driver of breast cancer progression associated with worse prognosis and more aggressive disease
We demonstrate that Human epidermal growth factor receptor 2 (HER2) overexpression enhances the cellular response to hypoxia, including the upregulation of genes implicated in driving breast cancer progression, and establish that growth factor signalling through HER2 is able to drive an oxygen-independent upregulation of Hypoxia-inducible factor 2 alpha (HIF-2α) through mechanisms different to those previously shown for Hypoxia-inducible factor 1 alpha (HIF-1α)
The differences in hypoxia-inducible factor (HIF)-1α and HIF-2α gene expression across molecular subtypes suggests that these factors are regulated in ways which allow subtype-specific differences in their expression, and in the case of HIF-2α this appears to be specific to the HER2-positive subtype
Summary
Tumour hypoxia is a driver of breast cancer progression associated with worse prognosis and more aggressive disease. The cellular response to hypoxia is mediated by the hypoxia-inducible transcription factors HIF-1 and HIF-2, whose transcriptional activity is canonically regulated through their oxygen-labile HIF-α subunits. These are constitutively degraded in the presence of oxygen; HIF-1α can be stabilised, even at high oxygen concentrations, through the activation of HER receptor signalling. PHD-mediated hydroxylation of HIF-α is restricted by the low availability of molecular oxygen This results in an accumulation of HIF-α subunits, which are able to form active dimers with HIF-β and drive the transcription of hypoxia response genes [7,8,9]
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