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PP2A and E3 ubiquitin ligase deficiencies: Seminal biological drivers in endometrial cancer

Jesus Gonzalez-Bosquet1, Jamie N Bakkum-Gamez2, Amy L Weaver3

  • 1Department of Obstetrics and Gynecology, University of Iowa, Iowa City, IA, United States of America.

Gynecologic Oncology
|April 19, 2021
PubMed
Abstract

Insights

Endometrial cancer (EC) involves PI3K-AKT pathway mutations. Deficiencies in protein phosphatase 2A (PP2A) and E3 ubiquitin ligase (E3UL) drive EC progression, independent of common mutations, impacting patient outcomes.

Area of Science:

  • Oncology
  • Molecular Biology
  • Genetics

Background:

  • Endometrial cancer (EC) is characterized by mutations in the PI3K-AKT pathway, a critical signaling cascade.
  • Kinase activity alone rarely drives oncogenesis; dysregulation of opposing phosphatases is crucial for pathway activation.
  • Understanding the interplay between kinases and phosphatases in EC is vital for identifying prognostic markers and therapeutic targets.

Purpose of the Study:

  • To investigate the interactions between PI3K-AKT pathway components and antagonistic phosphatases in endometrial cancer.
  • To correlate these molecular interactions with clinical outcomes, specifically progression-free survival (PFS).

Main Methods:

  • Analysis of The Cancer Genome Atlas (TCGA) EC cohort (n=209), excluding POLE mutations.
  • Integration of DNA sequencing, RNA expression, and copy number variation (CNV) data.
  • Correlation of PIK3CA, PTEN, PIK3R1 mutations, PIK3CA CNV, and expression of CIP2A (PP2A inhibitor) and FBXW7 (E3UL) with PFS.

Main Results:

  • 83% of patients had mutations in PIK3CA, PTEN, or PIK3R1, with 57% having multiple mutations, but this did not significantly impact PFS.
  • PIK3CA copy number variations (CNV) were linked to TP53 mutations and CIP2A expression but not PFS.
  • Impaired protein phosphatase 2A (PP2A) and E3 ubiquitin ligase (E3UL) function, indicated by CIP2A overexpression or specific mutations, were significantly associated with compromised PFS and were prognostic for PIK3CA-altered tumors.

Conclusions:

  • Deficiencies in PP2A and E3UL are key drivers of endometrial cancer progression.
  • These deficiencies are biologically significant in EC, irrespective of PIK3CA, PTEN, or PIK3R1 mutations or PIK3CA CNV.
  • Targeting PP2A and E3UL pathways may offer novel therapeutic strategies for endometrial cancer.
Keywords:
CIP2AFBXW7PIK3CAPIK3R1APP2APPP2R1APTEN

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