Somatic single hits inactivate the X-linked tumor suppressor FOXP3 in the prostate

Lizhong Wang1, Runhua Liu, Weiquan Li

  • 1Division of Immunotherapy, Department of Surgery, University of Michigan School of Medicine and Cancer Center, Ann Arbor, MI 48109, USA.

Cancer Cell
|October 6, 2009
PubMed

Insights

The FOXP3 gene on the X chromosome acts as a prostate tumor suppressor. Inactivating mutations in FOXP3 drive prostate cancer by allowing the oncogene cMYC to overexpress.

Area of Science:

  • Oncology
  • Genetics
  • Molecular Biology

Background:

  • Prostate cancer genetics research has primarily focused on autosomal genes.
  • Epidemiological and genetic data suggest a role for X-linked factors in prostate cancer risk.

Purpose of the Study:

  • To investigate the role of X-linked genes in prostate cancer.
  • To identify specific X-linked genes involved in prostate tumorigenesis.

Main Methods:

  • Analysis of somatic mutations and deletions in the X-linked FOXP3 gene in human prostate cancer tissues.
  • Lineage-specific ablation of FoxP3 in mouse prostate epithelial cells.
  • Investigation of FOXP3's transcriptional regulation of cMYC.

Main Results:

  • Somatic inactivating mutations and deletion of the X-linked FOXP3 gene were identified in human prostate cancer.
  • FoxP3 ablation in mouse prostate epithelial cells induced hyperplasia and intraepithelial neoplasia.
  • FOXP3 was found to be necessary and sufficient to repress cMYC expression.

Conclusions:

  • FOXP3 functions as an X-linked prostate tumor suppressor in males.
  • Inactivation of FOXP3 contributes to prostate carcinogenesis through the dysregulation of cMYC.
  • This study presents a paradigm of single genetic hit inactivation in X-linked carcinogenesis.

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