Abstract
BackgroundOncogene overexpression in primary cells often triggers the induction of a cellular safeguard response promoting senescence or apoptosis. Secondary cooperating genetic events are generally required for oncogene-induced tumorigenesis to overcome these biologic obstacles. We employed comparative genomic hybridization for eight genetically engineered mouse models of mammary cancer to identify loci that might harbor genes that enhance oncogene-induced tumorigenesis.ResultsUnlike many other mammary tumor models, the MMTV-Myc tumors displayed few copy number variants except for amplification of distal mouse chromosome 11 in 80 % of the tumors (syntenic to human 17q23-qter often amplified in human breast cancer). Analyses of candidate genes located in this region identified JMJD6 as an epigenetic regulatory gene that cooperates with Myc to enhance tumorigenesis. It suppresses Myc-induced apoptosis under varying stress conditions through inhibition of p19ARF messenger RNA (mRNA) and protein, leading to reduced levels of p53. JMJD6 binds to the p19ARF promoter and exerts its inhibitory function through demethylation of H4R3me2a. JMJD6 overexpression in MMTV-Myc cell lines increases tumor burden, induces EMT, and greatly enhances tumor metastasis. Importantly, we demonstrate that co-expression of high levels of JMJD6 and Myc is associated with poor prognosis for human ER+ breast cancer patients.ConclusionsA novel epigenetic mechanism has been identified for how JMJD6 cooperates with Myc during oncogenic transformation. Combined high expression of Myc and JMJD6 confers a more aggressive phenotype in mouse and human tumors. Given the pleiotropic pro-tumorigenic activities of JMJD6, it may be useful as a prognostic factor and a therapeutic target for Myc-driven mammary tumorigenesis.Electronic supplementary materialThe online version of this article (doi:10.1186/s13148-016-0205-6) contains supplementary material, which is available to authorized users.
Highlights
Oncogene overexpression in primary cells often triggers the induction of a cellular safeguard response promoting senescence or apoptosis
Identification of JMJD6 as a gene that cooperates with Myc to enhance tumorigenesis could provide a novel therapeutic target for breast and other cancers where Myc is an essential driver of tumorigenesis, since to date no successful therapies directly targeting Myc have been developed
Identification of a chromosome 11 amplicon as the major genomic alteration in MMTV-Myc mammary tumors We performed comparative genomic hybridization (CGH) of mammary gland tumors from eight genetically engineered mouse models to identify genomic loci containing genes with altered expression that potentially cooperate with oncogenes or suppressor genes in promoting tumorigenesis
Summary
Oncogene overexpression in primary cells often triggers the induction of a cellular safeguard response promoting senescence or apoptosis. Secondary cooperating genetic events are generally required for oncogene-induced tumorigenesis to overcome these biologic obstacles. We employed comparative genomic hybridization for eight genetically engineered mouse models of mammary cancer to identify loci that might harbor genes that enhance oncogene-induced tumorigenesis. Initiating oncogenic alterations in untransformed cells in most, if not all cases, trigger cellular safeguard mechanisms that induce cellular senescence (e.g., Ras) or apoptosis (e.g., Myc, E2F1, or E1A). Oncogene-induced tumorigenesis generally requires cooperating genetic events to overcome these safeguard mechanisms. It has been firmly established that many genetically engineered mouse models (GEMs) of mammary cancer are valuable systems to dissect tumorigenic pathways that may involve multiple genetic aberrations. Many models have been designed to mimic human breast cancer by either overexpression of known oncogenes (Myc, Aprelikova et al Clinical Epigenetics (2016) 8:38
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