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Christensen, Camilla

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Christensen

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Camilla

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Christensen, Camilla

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2013 - 20172

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Author's Publications: search.filters.isAuthorOfPublication.b7aa991e-9172-4fb5-b84c-1e6ab7be7abf

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    MUC1-C activates EZH2 expression and function in human cancer cells
    (Nature Publishing Group UK, 2017) Rajabi, Hasan; Hiraki, Masayuki; Tagde, Ashujit; Alam, Maroof; Bouillez, Audrey; Christensen, Camilla; Samur, Mehmet; Wong, Kwok-Kin; Kufe, Donald
    The EZH2 histone methyltransferase is a member of the polycomb repressive complex 2 (PRC2) that is highly expressed in diverse human cancers and is associated with a poor prognosis. MUC1-C is an oncoprotein that is similarly overexpressed in carcinomas and has been linked to epigenetic regulation. A role for MUC1-C in regulating EZH2 and histone methylation is not known. Here, we demonstrate that targeting MUC1-C in diverse human carcinoma cells downregulates EZH2 and other PRC2 components. MUC1-C activates (i) the EZH2 promoter through induction of the pRB→E2F pathway, and (ii) an NF-κB p65 driven enhancer in exon 1. We also show that MUC1-C binds directly to the EZH2 CXC region adjacent to the catalytic SET domain and associates with EZH2 on the CDH1 and BRCA1 promoters. In concert with these results, targeting MUC1-C downregulates EZH2 function as evidenced by (i) global and promoter-specific decreases in H3K27 trimethylation (H3K27me3), and (ii) activation of tumor suppressor genes, including BRCA1. These findings highlight a previously unreported role for MUC1-C in activating EZH2 expression and function in cancer cells.
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    Activation of the PD-1 Pathway Contributes to Immune Escape in EGFR-Driven Lung Tumors
    (American Association for Cancer Research (AACR), 2013) Akbay, Esra A.; Koyama, S.; Carretero, J.; Altabef, A.; Tchaicha, J. H.; Christensen, Camilla; Mikse, O. R.; Cherniack, Andrew; Beauchamp, Ellen; Pugh, Trevor J.; Wilkerson, M. D.; Fecci, Peter; Butaney, M.; Reibel, J. B.; Soucheray, M.; Cohoon, T. J.; Janne, Pasi; Meyerson, Matthew; Hayes, D. N.; Shapiro, Geoffrey; Shimamura, Takeshi; Sholl, Lynette; Rodig, Scott; Freeman, Gordon; Hammerman, Peter S.; Dranoff, Glenn; Wong, Kwok-Kin
    The success in lung cancer therapy with Programmed Death (PD)-1 blockade suggests that immune escape mechanisms contribute to lung tumor pathogenesis. We identified a correlation between Epidermal Growth Factor Receptor (EGFR) pathway activation and a signature of immunosuppression manifested by upregulation of PD-1, PD-L1, cytotoxic T lymphocyte antigen-4 (CTLA-4), and multiple tumor-promoting inflammatory cytokines. We observed decreased cytotoxic T cells and increased markers of T cell exhaustion in mouse models of EGFR-driven lung cancer. PD-1 antibody blockade improved the survival of mice with EGFR-driven adenocarcinomas by enhancing effector T cell function and lowering the levels of tumor-promoting cytokines. Expression of mutant EGFR in bronchial epithelial cells induced PD-L1, and PD-L1 expression was reduced by EGFR inhibitors in non-small cell lung cancer cell lines with activated EGFR. These data suggest that oncogenic EGFR signaling remodels the tumor microenvironment to trigger immune escape, and mechanistically link treatment response to PD-1 inhibition.