Targeted overexpression of EZH2 in the mammary gland disrupts ductal morphogenesis and causes epithelial hyperplasia

Am J Pathol. 2009 Sep;175(3):1246-54. doi: 10.2353/ajpath.2009.090042. Epub 2009 Aug 6.

Abstract

The Polycomb group protein enhancer of zeste homolog 2 (EZH2), which has roles during development of numerous tissues, is a critical regulator of cell type identity. Overexpression of EZH2 has been detected in invasive breast carcinoma tissue samples and is observed in human breast tissue samples of morphologically normal lobules up to 12 years before the development of breast cancer. The function of EZH2 during preneoplastic progression in the mammary gland is unknown. To investigate the role of EZH2 in the mammary gland, we targeted the expression of EZH2 to mammary epithelial cells using the mouse mammary tumor virus long terminal repeat. EZH2 overexpression resulted in aberrant terminal end bud architecture. By the age of 4 months, 100% of female mouse mammary tumor virus-EZH2 virgin mice developed intraductal epithelial hyperplasia resembling the human counterpart accompanied by premature differentiation of ductal epithelial cells and up-regulation of the luminal marker GATA-3. In addition, remodeling of the mammary gland after parturition was impaired and EZH2 overexpression caused delayed involution. Mechanistically, we found that EZH2 physically interacts with beta-catenin, inducing beta-catenin nuclear accumulation in mammary epithelial cells and activating Wnt/beta-catenin signaling. The biological significance of these data to human hyperplasias is demonstrated by EZH2 up-regulation and colocalization with beta-catenin in human intraductal epithelial hyperplasia, the earliest histologically identifiable precursor of breast carcinoma.

Publication types

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

MeSH terms

  • Age Factors
  • Animals
  • Breast Neoplasms / genetics
  • Cell Transformation, Neoplastic / genetics
  • Enhancer of Zeste Homolog 2 Protein
  • Female
  • GATA3 Transcription Factor / metabolism
  • Genetic Vectors
  • Histone-Lysine N-Methyltransferase / biosynthesis*
  • Histone-Lysine N-Methyltransferase / genetics
  • Humans
  • Hyperplasia / genetics
  • Mammary Glands, Animal / embryology
  • Mammary Glands, Animal / metabolism*
  • Mammary Glands, Animal / pathology*
  • Mammary Tumor Virus, Mouse
  • Mice
  • Mice, Transgenic
  • Morphogenesis / genetics
  • Polycomb Repressive Complex 2
  • Protein Binding
  • Signal Transduction
  • Transfection
  • Up-Regulation
  • beta Catenin / metabolism

Substances

  • GATA3 Transcription Factor
  • Gata3 protein, mouse
  • beta Catenin
  • Enhancer of Zeste Homolog 2 Protein
  • Ezh2 protein, mouse
  • Histone-Lysine N-Methyltransferase
  • Polycomb Repressive Complex 2