Abstract

Tumor progression is intrinsically tied to the clonal
selection of tumor cells with acquired phenotypes allowing
to cope with a hostile microenvironment. Hypoxiainducible
factors (HIFs) master the transcriptional
response to local tissue hypoxia, a hallmark of solid
tumors. Here, we report significantly longer patient
survival in breast cancer with high levels of HIF-2a.
Amphiregulin (AREG) and WNT1-inducible signaling
pathway protein-2 (WISP2) expression was strongly HIF-
2a-dependent and their promoters were particularly
responsive to HIF-2a. The endogenous AREG promoter
recruited HIF-2a in the absence of a classical HIF–DNA
interaction motif, revealing a novel mechanism of gene
regulation. Loss of AREG expression in HIF-2a-depleted
cells was accompanied by reduced activation of epidermal
growth factor (EGF) receptor family members. Apparently
opposing results from patient and in vitro data point
to an HIF-2a-dependent auto-stimulatory tumor phenotype
that, while promoting EGF signaling in cellular
models, increased the survival of diagnosed and treated
human patients. Our findings suggest a model where HIF-
2a-mediated autocrine growth signaling in breast cancer
sustains a state of cellular self-sufficiency, thereby
masking unfavorable microenvironmental growth conditions,
limiting adverse selection and improving therapy
efficacy. Importantly, HIF-2a/AREG/WISP2-expressing
tumors were associated with luminal tumor differentiation,
indicative of a better response to classical treatments.
Shifting the HIF-1/2a balance toward an HIF-2-
dominated phenotype could thus offer a novel approach in
breast cancer therapy.