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

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 112; no. 45; pp. E6215 - E6223
• Main Authors: Zhang, Huimin, Lu, Haiquan, Xiang, Lisha, Bullen, John W., Zhang, Chuanzhao, Samanta, Debangshu, Gilkes, Daniele M., He, Jianjun, Semenza, Gregg L.
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences 10.11.2015; National Acad Sciences
• Series: PNAS Plus
• Subjects: Analysis of Variance; Biological Sciences; Breast cancer; Breast Neoplasms - metabolism; CD47 Antigen - metabolism; Cell Line, Tumor; Chromatin Immunoprecipitation; Correlation analysis; DNA Primers; Female; Gene expression; Gene Expression Regulation, Neoplastic - drug effects; Gene Expression Regulation, Neoplastic - physiology; Genotype & phenotype; Humans; Hypoxia; Hypoxia-Inducible Factor 1 - metabolism; Hypoxia-Inducible Factor 1 - pharmacology; Immunoblotting; Luciferases; Neoplastic Stem Cells - physiology; Phagocytosis - physiology; PNAS Plus; Real-Time Polymerase Chain Reaction; RNA, Small Interfering - genetics; Stem cells; Tumor Escape - physiology; “don’t eat me” signal; tumor-initiating cells; tumor microenvironment; immune evasion; antitumor immunity
• ISSN: 0027-8424; 1091-6490; 1091-6490
• DOI: 10.1073/pnas.1520032112

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 theCD47gene 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.