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Endometrial PTEN Deficiency Leads to SMAD2/3 Nuclear Translocation

Núria Eritja1, Raúl Navaridas1, Anna Ruiz-Mitjana1

  • 1Oncologic Pathology Group, Departament de Ciències Mèdiques Bàsiques, Institut de Recerca Biomèdica de Lleida, IRBLleida, Universitat de Lleida, Centro de Investigación Biomédica en Red Cáncer CIBERONC, 25198 Lleida, Spain.

Cancers
|October 13, 2021
PubMed

Insights

Loss of PTEN in endometrial cells causes SMAD2/3 to move into the nucleus, which surprisingly constrains tumor growth. This suggests a complex role for SMAD2/3 in PTEN-deficient endometrial carcinogenesis.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cell Biology

Background:

  • Transforming Growth Factor-beta (TGF-β) exhibits dual roles in cancer, acting as a tumor suppressor in early stages and a promoter in advanced cancers.
  • The TGF-β/SMAD and PI3K/PTEN/AKT signaling pathways are crucial for endometrial epithelial cell homeostasis, and their dysregulation contributes to endometrial carcinogenesis.
  • Previous studies indicated tumor-suppressive functions for PTEN and SMAD2/3 in the endometrium, with PTEN deficiency promoting proliferation and inhibiting TGF-β-induced apoptosis.

Purpose of the Study:

  • To investigate the molecular and cellular effects of PTEN deficiency on TGF-β/SMAD2/3 signaling in endometrial carcinogenesis.
  • To determine the functional role of nuclear SMAD2/3 translocation in PTEN-deficient endometrial cells.

Main Methods:

  • Utilized an in vitro and in vivo model of endometrial carcinogenesis.
  • Generated mouse endometrial organoids with combined PTEN and SMAD2/3 gene deletions.
  • Analyzed SMAD2/3 nuclear translocation and its downstream effects on cell proliferation and organoid growth.

Main Results:

  • Loss of PTEN in endometrial cells led to constitutive nuclear translocation of SMAD2/3.
  • Double deletion of PTEN and SMAD2/3 resulted in significantly increased cell proliferation and larger endometrial organoids compared to PTEN-deficient organoids.
  • These findings suggest that nuclear SMAD2/3 acts as a brake on the tumorigenesis initiated by PTEN deficiency.

Conclusions:

  • Nuclear translocation of SMAD2/3, induced by PTEN deficiency, paradoxically constrains endometrial tumorigenesis.
  • The interplay between PTEN, SMAD2/3, and TGF-β signaling is complex and context-dependent in endometrial cancer.
  • Targeting this pathway could offer novel therapeutic strategies for endometrial cancer.
Keywords:
PTENSMAD2/3TGF-βendometrial cancer

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