HER2 Overexpression Modifies the Cellular Response to Hypoxia in MCF7 Breast Cancer Cell Lines

ABSTRACT: Tumour hypoxia is a recognised driver of breast cancer pathology. The main cellular response to hypoxia is mediated by the hypoxia-inducible factors HIF1 and HIF2, and is controlled through the regulation of oxygen-labile HIFα subunits. HIF1α has a well-established role in breast cancer where it has also been shown to be regulated by growth factor signalling. However, the role of HIF2α has been less thoroughly researched. Here, the role of HIF2α was investigated in breast cancer cell lines and publicly available gene expression datasets to determine its relationship with HER2 receptor expression in breast cancer. Using an isogenic cell line model for HER2 overexpression, we establish a direct role for HER2 in driving HIF2α expression in breast cancer. The effect of HER2-mediated HIF2α expression on the cellular response to acute and chronic hypoxia was investigated in 2D and 3D cell line models, and through protein and gene expression analysis, HER2 was shown to drive an exacerbated hypoxic response in these cells. In growth assays, HER2-overexpressing cell lines were shown to be highly sensitive to HIF2-specific inhibition through HIF2α-targeted siRNA and treatment with the HIF2α-specific translation inhibitor C76. Additionally, survival analysis in a large, publicly available dataset demonstrated a relationship between HIF2α and poor disease-specific survival in HER2-overexpressing tumours. We demonstrate a novel role for HIF2α in driving an increased hypoxic response in breast cancer cells and suggest HIF2 signalling may be an important, targetable pathway in HER2-positive breast cancers.

ORGANISM(S): Homo sapiens

PROVIDER: GSE111246 | GEO | 2018/03/01

REPOSITORIES: GEO