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FOXP3 is a novel transcriptional repressor for the breast cancer oncogene SKP2

Tao Zuo1, Runhua Liu, Huiming Zhang

  • 1Department of Surgery, Section of General Surgery, University of Michigan, Ann Arbor, Michigan, USA.

The Journal of Clinical Investigation
|November 17, 2007
PubMed

Insights

Forkhead box P3 (FOXP3) acts as a tumor suppressor by directly repressing the oncogene S-phase kinase-associated protein 2 (SKP2). This downregulation of SKP2 is crucial for FOXP3

Area of Science:

  • Oncology
  • Molecular Biology
  • Genetics

Background:

  • S-phase kinase-associated protein 2 (SKP2) is a key component of the SKP1-Cul1-Fbox E3 ubiquitin ligase complex.
  • Overexpression of SKP2 is linked to cell cycle dysregulation and the development of various cancers.
  • Forkhead box P3 (FOXP3) is recognized as an X-linked breast cancer suppressor and a repressor of the ERBB2/HER2 oncogene.

Purpose of the Study:

  • To investigate novel targets of FOXP3 involved in its tumor suppressor activity beyond ERBB2/HER2.
  • To determine the relationship between FOXP3 and SKP2 expression in breast cancer.
  • To elucidate the mechanism by which FOXP3 regulates SKP2.

Main Methods:

  • Analysis of Skp2 expression in mouse mammary carcinomas with Foxp3 mutations.
  • In vitro studies involving ectopic FOXP3 expression and siRNA-mediated FOXP3 knockdown in cancer and epithelial cells.
  • Chromatin immunoprecipitation and reporter assays to assess direct promoter interaction.
  • Correlation analysis of FOXP3 and SKP2 levels in human breast cancer samples.

Main Results:

  • Mammary tumors from mice heterozygous for a Foxp3 mutation showed increased Skp2 expression.
  • FOXP3 expression repressed SKP2, leading to increased p27 levels and polyploidy in mouse mammary cancer cells.
  • FOXP3 directly repressed the Skp2 promoter, and an inverse correlation between FOXP3 and SKP2 was observed in human breast cancers.
  • Downregulation of SKP2 by FOXP3 was essential for growth inhibition in breast cancer cells lacking ERBB2/HER2 overexpression.

Conclusions:

  • FOXP3 functions as a novel transcriptional repressor of the oncogene SKP2.
  • The FOXP3-SKP2 regulatory axis represents a new mechanism for tumor suppression in breast cancer.
  • Targeting the SKP2 oncogene may be a therapeutic strategy for FOXP3-mediated breast cancer treatment.

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