Hypoxia-inducible factor (HIF) 1α and 2α are
transcription factors responsible for the cellular response to
hypoxia. The functional roles of HIF1α and HIF2α in
cancer are distinct and vary among different
tumor types. The aim of this study was to evaluate the compartment-specific role(s) of HIF1α and HIF2α in
breast cancer. To this end, immortalized human fibroblasts and MDA-MB-231
breast cancer cells carrying constitutively active HIF1α or HIF2α mutants were analyzed with respect to their metabolic function(s) and ability to promote
tumor growth in an in vivo setting. We observed that activation of HIF1α, but not HIF2α, in stromal cells promotes a shift toward aerobic glycolysis, with increased L-
lactate production and a loss of mitochondrial activity. In a xenograft model, HIF1α-activated fibroblasts promoted the
tumor growth of co-injected MDA-MB-231 cells without an increase in angiogenesis. Conversely, HIF2α-activated stromal cells did not favor
tumor growth and behaved as the empty vector controls. Similarly, activation of HIF1α, but not HIF2α, in MDA-MB-231 cells promoted a shift toward aerobic glycolysis, with increased
glucose uptake and L-
lactate production. In contrast, HIF2α activation in
cancer cells increased the expression of EGFR, Ras and
cyclin D1, which are known markers of
tumor growth and cell cycle progression. In a xenograft model, HIF1α activation in MDA-MB-231 cells acted as a
tumor suppressor, resulting in an almost 2-fold reduction in
tumor mass and volume. Interestingly, HIF2α activation in MDA-MB-231 cells induced a significant ~2-fold-increase in
tumor mass and volume. Analysis of mitochondrial activity in these
tumor xenografts using COX (
cytochrome C oxidase) staining demonstrated elevated mitochondrial oxidative metabolism (OXPHOS) in HIF2α-tumors. We conclude that the role(s) of HIF1α and HIF2α in
tumorigenesis are compartment-specific. HIF1α acts as a
tumor promoter in stromal cells but as a
tumor suppressor in
cancer cells. Conversely, HIF2α is a
tumor promoter in
cancer cells. Mechanistically, HIF1α-driven aerobic glycolysis in stromal cells supports
cancer cell growth via the paracrine production of nutrients (such as L-
lactate) that can "feed"
cancer cells. However, HIF1α-driven aerobic glycolysis in
cancer cells inhibits
tumor growth. Finally, HIF2α activation in
cancer cells induces the expression of known pro-oncogenic molecules and promotes the mitochondrial activity of
cancer cells.