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Indirect Immunofluorescence on Frozen Sections of Mouse Mammary Gland
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The Ron receptor tyrosine kinase negatively regulates mammary gland branching morphogenesis

Sara E Meyer1, Glendon M Zinser, William D Stuart

  • 1Department of Cancer and Cell Biology, Vontz Center for Molecular Studies, University of Cincinnati College of Medicine, 3125 Eden Ave, Cincinnati, OH 45267-0521, USA.

Developmental Biology
|July 7, 2009
PubMed

Insights

The Ron receptor tyrosine kinase negatively regulates mammary gland development. Ablating its tyrosine kinase domain accelerates pubertal development, increasing ductal branching through MAPK signaling.

Area of Science:

  • Developmental Biology
  • Molecular Biology
  • Oncology

Background:

  • The Ron receptor tyrosine kinase (RTK) is present in normal breast tissue.
  • RTK is overexpressed in about 50% of human breast cancers.
  • The role of Ron in normal mammary gland development is unknown.

Purpose of the Study:

  • To investigate the functional significance of Ron in normal mammary gland development.
  • To compare mammary gland development in wild-type mice and mice with targeted ablation of the Ron tyrosine kinase (TK) signaling domain (TK-/-).

Main Methods:

  • Comparison of mammary gland development in wild-type and RonTK-/- mice.
  • Analysis of epithelial cell turnover, circulating hormone levels, and MAPK phosphorylation.
  • Ex vivo culture of purified epithelial cells and MAPK inhibition.
  • Microarray analysis of pubertal mammary glands.

Main Results:

  • RonTK-/- mice exhibited accelerated pubertal development with increased ductal extension and branching morphogenesis.
  • Increased MAPK phosphorylation in the epithelium correlated with enhanced branching.
  • Ex vivo RonTK-/- epithelial cells showed enhanced branching, which was attenuated by MAPK inhibition.
  • Microarray analysis identified 393 genes temporally affected by Ron expression, impacting development, morphogenesis, differentiation, cell motility, and adhesion signaling networks.

Conclusions:

  • The Ron receptor tyrosine kinase acts as a critical negative regulator of mammary gland development.
  • Ron signaling influences ductal morphogenesis and branching through MAPK pathways.
  • These findings provide new insights into the molecular mechanisms governing normal breast development and potential therapeutic targets in breast cancer.

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