XMicroRNA-antagonism regulates breast cancer stemness and metastasis via TET-family-dependent chromatin remodeling Academic Article uri icon

Overview

MeSH Major

  • Breast Neoplasms
  • Chromatin Assembly and Disassembly
  • Epithelial-Mesenchymal Transition
  • Gene Expression Regulation, Neoplastic
  • MicroRNAs
  • Neoplasm Metastasis
  • Neoplastic Stem Cells

abstract

  • Tumor cells metastasize to distant organs through genetic and epigenetic alterations, including changes in microRNA (miR) expression. Here we find miR-22 triggers epithelial-mesenchymal transition (EMT), enhances invasiveness and promotes metastasis inĀ mouse xenografts. In a conditional mammary gland-specific transgenic (TG) mouse model, we show that miR-22 enhances mammary gland side-branching, expands the stem cell compartment, and promotes tumor development. Critically, miR-22 promotes aggressive metastatic disease in MMTV-miR-22 TG mice, as well as compound MMTV-neu or -PyVT-miR-22 TG mice. We demonstrate that miR-22 exerts its metastatic potential by silencing antimetastatic miR-200 through direct targeting of the TET (Ten eleven translocation) family of methylcytosine dioxygenases, thereby inhibiting demethylation of the mir-200 promoter. Finally, we show that miR-22 overexpression correlates with poor clinical outcomes and silencing of the TET-miR-200 axis in patients. Taken together, our findings implicate miR-22 as a crucial epigenetic modifier and promoterĀ of EMT and breast cancer stemness toward metastasis.

publication date

  • July 18, 2013

Research

keywords

  • Academic Article

Identity

Language

  • eng

PubMed Central ID

  • PMC3767157

Digital Object Identifier (DOI)

  • 10.1016/j.cell.2013.06.026

PubMed ID

  • 23830207

Additional Document Info

start page

  • 311

end page

  • 24

volume

  • 154

number

  • 2