CoREST1 promotes tumor formation and tumor stroma interactions in a mouse model of breast cancer

PLoS One. 2015 Mar 20;10(3):e0121281. doi: 10.1371/journal.pone.0121281. eCollection 2015.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Carcinogenesis / metabolism
  • Carcinogenesis / pathology*
  • Cell Communication*
  • Cell Line, Tumor
  • Cell Movement
  • Disease Models, Animal
  • Female
  • Gene Expression Regulation, Neoplastic
  • Gene Knockdown Techniques
  • Human Umbilical Vein Endothelial Cells / metabolism
  • Humans
  • Macrophage Activation
  • Macrophages / metabolism
  • Mammary Neoplasms, Animal / blood supply
  • Mammary Neoplasms, Animal / genetics
  • Mammary Neoplasms, Animal / metabolism*
  • Mammary Neoplasms, Animal / pathology*
  • Mice
  • Neovascularization, Pathologic / metabolism
  • Nerve Tissue Proteins / genetics
  • Nerve Tissue Proteins / metabolism*
  • Repressor Proteins / genetics
  • Repressor Proteins / metabolism*
  • Stromal Cells / metabolism
  • Stromal Cells / pathology
  • Xenograft Model Antitumor Assays

Substances

  • Nerve Tissue Proteins
  • Rcor2 protein, mouse
  • Repressor Proteins