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Effect of glycogen synthase kinase-3 inactivation on mouse mammary gland development and oncogenesis

J Dembowy1, H A Adissu2, J C Liu3

  • 11] Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada [2] Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada.

Oncogene
|September 9, 2014
PubMed

Insights

Glycogen synthase kinase-3 (GSK-3) is crucial for mammary gland development and tumor suppression. Its deletion activates Wnt signaling, leading to mammary tumors and altered stem cell properties.

Area of Science:

  • Cellular and Molecular Biology
  • Developmental Biology
  • Cancer Research

Background:

  • Wnt/β-catenin signaling is vital for mammary gland development and tumorigenesis.
  • The specific roles of glycogen synthase kinase-3 (GSK-3α and GSK-3β) in mammopoiesis and oncogenesis remain largely undefined.

Purpose of the Study:

  • To investigate the contribution of GSK-3 to mammary gland development and tumorigenesis.
  • To elucidate the β-catenin-dependent and -independent functions of GSK-3 in the mammary epithelium.

Main Methods:

  • Mammary-specific knockout of GSK-3 using WAP-Cre.
  • Generation of mammary-specific double knockouts of GSK-3 and β-catenin.
  • Histological analysis and assessment of mammary stem cell properties (mammosphere formation).

Main Results:

  • Deletion of GSK-3 in mammary epithelium activates Wnt/β-catenin signaling, inducing mammary intraepithelial neoplasia and adenosquamous carcinomas.
  • Loss of GSK-3 and β-catenin attenuates squamous transdifferentiation but impairs mammary epithelial stem cell function.
  • Tumors lacking GSK-3 and β-catenin exhibit elevated γ-catenin/plakoglobin and activated Hedgehog and Notch pathways.

Conclusions:

  • GSK-3 isoforms are essential regulators of mammary gland development and suppress tumorigenesis.
  • GSK-3 integrates multiple signaling pathways, including Wnt, Hedgehog, and Notch, to maintain mammary gland homeostasis.
  • GSK-3 plays critical roles in both β-catenin-dependent and -independent pathways governing mammary epithelial stem cell function.

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