title: CoREST1 promotes tumor formation and tumor stroma interactions in a mouse model of breast cancer.
abstract: 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.
authors: Department of Developmental, Molecular and Chemical Biology, Sackler School of Graduate Biomedical Sciences, Tufts University School of Medicine, Boston, Massachusetts, United States of America; Genetics Program, Sackler School of Graduate Biomedical Sciences, Tufts University School of Medicine, Boston, Massachusetts, United States of America.
authors: Sohini
authors: S
authors: Mazumdar
authors: Department of Developmental, Molecular and Chemical Biology, Sackler School of Graduate Biomedical Sciences, Tufts University School of Medicine, Boston, Massachusetts, United States of America; Molecular Oncology Research Institute, Tufts Medical Center, Boston, Massachusetts, United States of America.
authors: Lisa M
authors: LM
authors: Arendt
authors: Department of Developmental, Molecular and Chemical Biology, Sackler School of Graduate Biomedical Sciences, Tufts University School of Medicine, Boston, Massachusetts, United States of America; Genetics Program, Sackler School of Graduate Biomedical Sciences, Tufts University School of Medicine, Boston, Massachusetts, United States of America; Molecular Oncology Research Institute, Tufts Medical Center, Boston, Massachusetts, United States of America.
authors: Sarah
authors: S
authors: Phillips
authors: Department of Developmental, Molecular and Chemical Biology, Sackler School of Graduate Biomedical Sciences, Tufts University School of Medicine, Boston, Massachusetts, United States of America; Cellular, Molecular and Developmental Biology Program, Sackler School of Biomedical Sciences, Tufts University School of Medicine, Boston, Massachusetts, United States of America; Molecular Oncology Research Institute, Tufts Medical Center, Boston, Massachusetts, United States of America.
authors: Maja
authors: M
authors: Sedic
authors: Department of Developmental, Molecular and Chemical Biology, Sackler School of Graduate Biomedical Sciences, Tufts University School of Medicine, Boston, Massachusetts, United States of America; Molecular Oncology Research Institute, Tufts Medical Center, Boston, Massachusetts, United States of America.
authors: Charlotte
authors: C
authors: Kuperwasser
authors: Department of Developmental, Molecular and Chemical Biology, Sackler School of Graduate Biomedical Sciences, Tufts University School of Medicine, Boston, Massachusetts, United States of America.
authors: Grace
authors: G
authors: Gill
mesh_terms: D000818:Animals; D063646:Carcinogenesis / Q000378:metabolism / Q000473:pathology*; D002450:Cell Communication; D045744:Cell Line, Tumor; D002465:Cell Movement; D056970:Co-Repressor Proteins; D004195:Disease Models, Animal; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D055785:Gene Knockdown Techniques; D061307:Human Umbilical Vein Endothelial Cells / Q000378:metabolism; D006801:Humans; D008262:Macrophage Activation; D008264:Macrophages / Q000378:metabolism; D015674:Mammary Neoplasms, Animal / Q000098:blood supply / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D051379:Mice; D009389:Neovascularization, Pathologic / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism*; D017154:Stromal Cells / Q000378:metabolism / Q000473:pathology; D023041:Xenograft Model Antitumor Assays
chemical_list: D056970:Co-Repressor Proteins; D009419:Nerve Tissue Proteins; C485650:Rcor2 protein, mouse; D012097:Repressor Proteins