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HIF-1 Regulates CD47 Expression in Breast Cancer Cells to Promote

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HIF-1 Regulates CD47 Expression in Breast Cancer Cells to Promote HIF-1 regulates CD47 expression in breast cancer cells PNAS PLUS to promote evasion of phagocytosis and maintenance of cancer stem cells Huimin Zhanga,b,c, Haiquan Lub,c, Lisha Xiangb,c, John W. Bullenb,c, Chuanzhao Zhangb,c, Debangshu Samantab,c, Daniele M. Gilkesd, Jianjun Hea, and Gregg L. Semenzab,c,d,e,f,g,h,1 aDepartment of Breast Surgery, The First Affiliated Hospital of Xi’an Jiaotong University Health Science Center, Xi’an, Shaanxi 710061, China; bInstitute for Cell Engineering, The Johns Hopkins University School of Medicine, Baltimore, MD 21205; cMcKusick-Nathans Institute of Genetic Medicine, The Johns Hopkins University School of Medicine, Baltimore, MD 21205; dDepartment of Oncology, The Johns Hopkins University School of Medicine, Baltimore, MD 21205; eDepartment of Pediatrics, The Johns Hopkins University School of Medicine, Baltimore, MD 21205; fDepartment of Medicine, The Johns Hopkins University School of Medicine, Baltimore, MD 21205; gDepartment of Radiation Oncology, The Johns Hopkins University School of Medicine, Baltimore, MD 21205; and hDepartment of Biological Chemistry, The Johns Hopkins University School of Medicine, Baltimore, MD 21205 Contributed by Gregg L. Semenza, October 9, 2015 (sent for review September 18, 2015; reviewed by Shinae Kizaka-Kondoh and Michail V. Sitkovsky) Increased expression of CD47 has been reported to enable cancer phenotype (19, 20) through functional and physical interactions cells to evade phagocytosis by macrophages and to promote the of HIF-1 with the coactivator TAZ (20, 21) and by HIF-dependent cancer stem cell phenotype, but the molecular mechanisms regulat- expression of pluripotency factors (22). Hypoxia also induces im- ing CD47 expression have not been determined. Here we report mune evasion by several HIF-dependent mechanisms (23, 24). that hypoxia-inducible factor 1 (HIF-1) directly activates transcription A major mechanism by which cancer cells evade the innate im- CD47 of the gene in hypoxic breast cancer cells. Knockdown of HIF mune system is by expression of CD47, which is a cell-surface activity or CD47 expression increased the phagocytosis of breast protein that interacts with signal regulatory protein α (SIRPα)on cancer cells by bone marrow-derived macrophages. CD47 expression was increased in mammosphere cultures, which are enriched for the surface of macrophages to block phagocytosis (25, 26). Ex- cancer stem cells, and CD47 deficiency led to cancer stem cell de- pression of calreticulin (CRT) on the surface of cancer cells is pletion. Analysis of datasets derived from thousands of patients the primary trigger for phagocytosis by binding to low-density with breast cancer revealed that CD47 expression was correlated lipoprotein-related protein (LRP) on the surface of macro- with HIF target gene expression and with patient mortality. Thus, phages (27). The prophagocytic signal triggered by CRT–LRP CD47 expression contributes to the lethal breast cancer phenotype ligation is counterbalanced by the antiphagocytic signal trig- that is mediated by HIF-1. gered by CD47–SIRPα ligation (28). Analysis of circulating tumor cells isolated from the blood of patients with breast antitumor immunity | immune evasion | tumor-initiating cells | cancer revealed that CD47 expression identified a subpopula- “ ’ ” tumor microenvironment | don t eat me signal tion of cells with the capability to generate tumor xenografts in mice (29). Here, we report that CD47 expression is induced in a he pathogenesis of breast cancer reflects not only the con- HIF-dependent manner when human breast cancer cells are Tsequence of somatic mutations that dysregulate oncogenes and tumor suppressor genes, but also the effect of the changing exposed to hypoxia. Modest inhibition of CD47 expression was tumor microenvironment, particularly the development of intra- sufficient to increase the phagocytosis of breast cancer cells and decrease the number of breast CSCs. Human breast cancer tumoral hypoxia. The median pO2 within primary breast cancers is 10 mmHg (1.4% O2) compared with 65 mmHg (9.3% O2)in database analysis revealed that high CD47 expression is corre- normal breast tissue (1). Exposure of breast cancer cells to re- lated with increased HIF target gene expression and decreased duced O2 availability induces the activity of hypoxia-inducible patient survival. factors (HIFs), which are heterodimeric transcriptional activators, α α α consisting of an O2-regulated HIF-1 ,HIF-2 , or HIF-3 subunit Significance and a constitutively expressed HIF-1β subunit, that control the expression of hundreds of target genes (2). Increased expression of α Uncontrolled cell proliferation and abnormal blood vessel for- the HIF-1 subunit, detected by immunohistochemistry in primary mation result in regions of breast cancers that are hypoxic breast cancer biopsies, is associated with a significantly increased (deprived of oxygen). Hypoxia-inducible factors (HIFs) stimu- risk of metastasis and mortality (2). late the expression of genes that enable cancer cells to invade MEDICAL SCIENCES Preclinical studies in mouse models have demonstrated that α α and metastasize, leading to patient mortality. In this paper, we loss of HIF-1 or HIF-2 expression impairs the metastasis of report that HIFs stimulate the production of CD47, a protein on breast cancer cells to axillary lymph nodes (3), lungs (4, 5), and the cell surface that enables cancer cells to avoid destruction by bone (6, 7). Specific HIF target genes have been identified that macrophages. CD47 is also important for maintaining cancer are induced by hypoxia in breast cancer cells and promote stem cells, which are a small population of cells that are re- critical steps in the metastatic process, including stromal cell quired for the formation of primary tumors and metastases. recruitment (8, 9), cancer cell migration (10), invasion and Reduction of HIF activity or CD47 levels in breast cancer cells – intravasation (11 15), margination and extravasation (5), and led to increased killing by macrophages and depletion of can- premetastatic niche formation (12, 16). Increased expression of cer stem cells. HIF target genes in primary breast cancers is associated with increased patient mortality (17, 18). Author contributions: H.Z. and G.L.S. designed research; H.Z., H.L., L.X., J.W.B., C.Z., D.S., To give rise to a primary tumor, a tumor relapse, or a meta- and D.M.G. performed research; J.H. contributed new reagents/analytic tools; H.Z. and static tumor, a breast cancer cell must possess two important G.L.S. analyzed data; and H.Z. and G.L.S. wrote the paper. characteristics: first, the cell must avoid destruction by the im- Reviewers: S.K.-K., Tokyo Institute of Technology; and M.V.S., Northeastern University. mune system and, second, the cell must possess stem-cell–like The authors declare no conflict of interest. properties. Hypoxia induces the breast cancer stem cell (CSC) 1To whom correspondence should be addressed. Email: [email protected]. www.pnas.org/cgi/doi/10.1073/pnas.1520032112 PNAS | Published online October 28, 2015 | E6215–E6223 Downloaded by guest on September 26, 2021 Results is an immortalized but nontumorigenic mammary epithelial line; + + MCF7 is ER PR and tumorigenic but nonmetastatic; HCC1954 is Hypoxia Induces Increased CD47 Expression in a HIF-Dependent Manner. + HER2 and tumorigenic but nonmetastatic; and MDA-MB-231, Breast cancers are classified based on their expression of the estrogen − − − receptor (ER), progesterone receptor (PR), and human epidermal MDA-MB-435, and SUM159 are ER PR HER2 (i.e., triple growth factor receptor 2 (HER2); they are also classified according to negative), tumorigenic and metastatic. Reverse transcription (RT) expression of a 50-mRNA signature (PAM50) into luminal A, lu- and quantitative real-time PCR (qPCR) assays revealed that minal B, HER2-enriched, basal-like, and normal-like subgroups (30). expression of CD47 mRNA was significantly induced by We analyzed the effect of hypoxia (1% O2 for 24 h) on CD47 hypoxia in MCF7, HCC1954, MDA-MB-435, and SUM159 mRNA levels in six different human breast cell lines: MCF10A cells but not in MCF10A or MDA-MB-231 cells (Fig. 1A). ABCMCF7 HCC1954 MCF7 HCC1954 SUM159 D SUM159 E FGHMCF7 HCC1954 SUM159 20% O2 1% O2 20% O2 1% O2 NTC NTC NTC NTC 20% O2 DKD DKD DKD DKD 1% O2 ISO ISO ISO ISO ISO % of Max Fig. 1. Hypoxia induces CD47 expression in a HIF-dependent manner. (A) Reverse transcription (RT) and quantitative real-time PCR (qPCR) were performed to determine CD47 mRNA levels in human breast cell lines following exposure to 20% or 1% O2 for 24 h. For each sample, the expression of CD47 mRNA was quantified relative to 18S rRNA and then normalized to the result obtained from MCF-10A cells at 20% O2 (mean ± SEM; n = 3). Significant increase at 1% O2 compared with 20% O2:*P < 0.05, **P < 0.01, ***P < 0.001 (Student’s t test). (B and C) CD47 mRNA expression was analyzed by RT-qPCR in MCF7 (B) and HCC1954 (C) subclones expressing shRNA targeting HIF-1α (sh1α), HIF-2α (sh2α), or HIF-1α and HIF-2α (DKD), or expressing a nontargeting control shRNA (NTC), which were ## ### exposed to 20% or 1% O2 for 24 h. Data were normalized to NTC at 20% O2 (mean ± SEM; n = 3). **P < 0.01, ***P < 0.001 vs. NTC at 20% O2; P < 0.01, P < 0.001 vs. NTC at 1% O2 (two-way ANOVA with Bonferroni posttest). (D) SUM159 cells were treated with vehicle (Con) or 2.5 μM acriflavine (ACF), exposed to 20% or ## 1% O2 for 48 h, and expression of CD47 mRNA was assayed by RT-qPCR. ***P < 0.001 vs. Con at 20% O2; P < 0.01 vs. Con at 1% O2 (two-way ANOVA with Bonferroni posttest). (E) Immunoblot assays were performed to analyze HIF-2α,HIF-1α, CD47, and Actin protein expression in whole cell lysates prepared from MCF7 (Left) and HCC1954 (Middle) subclones exposed to 20% O2 (N) or 1% O2 (H) for 24 h, and lysates from SUM159 cells (Right), which were treated with vehicle (Con) or 2.5 μM acriflavine (ACF) and exposed to 20% or 1% O2 for 48 h.
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