RESUMO
Regulators of chromatin structure and gene expression contribute to tumor formation and progression. The co-repressor CoREST1 regulates the localization and activity of associated histone modifying enzymes including lysine specific demethylase 1 (LSD1) and histone deacetylase 1 (HDAC1). Although several CoREST1 associated proteins have been reported to enhance breast cancer progression, the role of CoREST1 in breast cancer is currently unclear. Here we report that knockdown of CoREST1 in the basal-type breast cancer cell line, MDA-MB-231, led to significantly reduced incidence and diminished size of tumors compared to controls in mouse xenograft studies. Notably, CoREST1-depleted cells gave rise to tumors with a marked decrease in angiogenesis. CoREST1 knockdown led to a decrease in secreted angiogenic and inflammatory factors, and mRNA analysis suggests that CoREST1 promotes expression of genes related to angiogenesis and inflammation including VEGF-A and CCL2. CoREST1 knockdown decreased the ability of MDA-MB-231 conditioned media to promote endothelial cell tube formation and migration. Further, tumors derived from CoREST1-depleted cells had reduced macrophage infiltration and the secretome of CoREST1 knockdown cells was deficient in promoting macrophage migration and macrophage-mediated angiogenesis. Taken together, these findings reveal that the epigenetic regulator CoREST1 promotes tumorigenesis in a breast cancer model at least in part through regulation of gene expression patterns in tumor cells that have profound non-cell autonomous effects on endothelial and inflammatory cells in the tumor microenvironment.
Assuntos
Carcinogênese/patologia , Comunicação Celular , Neoplasias Mamárias Animais/metabolismo , Neoplasias Mamárias Animais/patologia , Proteínas do Tecido Nervoso/metabolismo , Proteínas Repressoras/metabolismo , Animais , Carcinogênese/metabolismo , Linhagem Celular Tumoral , Movimento Celular , Proteínas Correpressoras , Modelos Animais de Doenças , Feminino , Regulação Neoplásica da Expressão Gênica , Técnicas de Silenciamento de Genes , Células Endoteliais da Veia Umbilical Humana/metabolismo , Humanos , Ativação de Macrófagos , Macrófagos/metabolismo , Neoplasias Mamárias Animais/irrigação sanguínea , Neoplasias Mamárias Animais/genética , Camundongos , Neovascularização Patológica/metabolismo , Proteínas do Tecido Nervoso/genética , Proteínas Repressoras/genética , Células Estromais/metabolismo , Células Estromais/patologia , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Perturbations in stem cell activity and differentiation can lead to developmental defects and cancer. We use an approach involving a quantitative model of cell-state transitions in vitro to gain insights into how SLUG/SNAI2, a key developmental transcription factor, modulates mammary epithelial stem cell activity and differentiation in vivo. In the absence of SLUG, stem cells fail to transition into basal progenitor cells, while existing basal progenitor cells undergo luminal differentiation; together, these changes result in abnormal mammary architecture and defects in tissue function. Furthermore, we show that in the absence of SLUG, mammary stem cell activity necessary for tissue regeneration and cancer initiation is lost. Mechanistically, SLUG regulates differentiation and cellular plasticity by recruiting the chromatin modifier lysine-specific demethylase 1 (LSD1) to promoters of lineage-specific genes to repress transcription. Together, these results demonstrate that SLUG plays a dual role in repressing luminal epithelial differentiation while unlocking stem cell transitions necessary for tumorigenesis.
Assuntos
Transformação Celular Neoplásica , Células-Tronco/metabolismo , Fatores de Transcrição/metabolismo , Animais , Diferenciação Celular , Linhagem Celular , Linhagem da Célula , Intervalo Livre de Doença , Regulação da Expressão Gênica , Histonas/metabolismo , Humanos , Glândulas Mamárias Humanas/citologia , Camundongos , Camundongos Endogâmicos NOD , Camundongos Knockout , Camundongos SCID , Neoplasias/metabolismo , Neoplasias/mortalidade , Neoplasias/patologia , Proteínas Proto-Oncogênicas c-myc/genética , Proteínas Proto-Oncogênicas c-myc/metabolismo , RNA Mensageiro/metabolismo , Regeneração , Fatores de Transcrição da Família Snail , Transplante de Células-Tronco , Células-Tronco/citologia , Fatores de Transcrição/antagonistas & inibidores , Fatores de Transcrição/genética , Transplante HeterólogoRESUMO
Raxibacumab (ABthrax) is a human IgG1 monoclonal antibody against Bacillus anthracis protective antigen. HGS is currently providing stockpiles of the agent to the US government for use in the prevention and treatment of inhalation anthrax. As of May 2009, the candidate was undergoing review by the US Food and Drug Administration. The availability of bioterrorism countermeasures has become more important since the September 2001 anthrax attacks, and development of raxibacumab is a significant advance in this area.
Assuntos
Antraz/terapia , Anticorpos Monoclonais/uso terapêutico , Bacillus anthracis/imunologia , Animais , Antraz/imunologia , Anticorpos Monoclonais Humanizados , Antígenos de Bactérias/imunologia , Bacillus anthracis/patogenicidade , Toxinas Bacterianas/antagonistas & inibidores , Bioterrorismo/prevenção & controle , Aprovação de Equipamentos , Humanos , Estados UnidosRESUMO
Golimumab, a human anti-TNFalpha IgG1kappa monoclonal antibody, was approved in the US and Canada in April 2009 as a treatment for rheumatoid arthritis, psoriatic arthritis and ankylosing spondylitis, and is undergoing regulatory review in the EU for these indications. The product was developed by Centocor and Janssen Pharmaceutical KK (Johnson & Johnson subsidiaries), in collaboration with Schering-Plough and Mitsubishi Tanabe Pharma. Golimumab faces numerous protein therapeutic competitors on the market, but, as the first patient-administered, once-monthly dosed anti-TNFalpha drug, it will likely be an attractive option for patients.
