HIF-1 regulates CD47 expression in breast cancer cells to promote evasion of phagocytosis and maintenance of cancer stem cells

TLDR

Increased CD47 expression enables cancer cells to evade macrophage phagocytosis and promotes a cancer stem cell phenotype, yet the mechanisms regulating CD47 remain unclear. HIF‑1 directly activates CD47 transcription in hypoxic breast cancer cells, and knockdown of HIF‑1 or CD47 enhances macrophage phagocytosis, depletes cancer stem cells, and is associated with reduced patient mortality, underscoring CD47’s role in a lethal, HIF‑1‑mediated breast cancer phenotype.

Abstract

Increased expression of CD47 has been reported to enable cancer cells to evade phagocytosis by macrophages and to promote the cancer stem cell phenotype, but the molecular mechanisms regulating CD47 expression have not been determined. Here we report that hypoxia-inducible factor 1 (HIF-1) directly activates transcription of the CD47 gene in hypoxic breast cancer cells. Knockdown of HIF activity or CD47 expression increased the phagocytosis of breast cancer cells by bone marrow-derived macrophages. CD47 expression was increased in mammosphere cultures, which are enriched for cancer stem cells, and CD47 deficiency led to cancer stem cell depletion. Analysis of datasets derived from thousands of patients with breast cancer revealed that CD47 expression was correlated with HIF target gene expression and with patient mortality. Thus, CD47 expression contributes to the lethal breast cancer phenotype that is mediated by HIF-1.