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

Cancer Cell. 2009 Oct 6;16(4):336-46. doi: 10.1016/j.ccr.2009.08.016.

Abstract

Despite clear epidemiological and genetic evidence for X-linked prostate cancer risk, all prostate cancer genes identified are autosomal. Here, we report somatic inactivating mutations and deletion of the X-linked FOXP3 gene residing at Xp11.23 in human prostate cancer. Lineage-specific ablation of FoxP3 in the mouse prostate epithelial cells leads to prostate hyperplasia and prostate intraepithelial neoplasia. In both normal and malignant prostate tissues, FOXP3 is both necessary and sufficient to transcriptionally repress cMYC, the most commonly overexpressed oncogene in prostate cancer as well as among the aggregates of other cancers. FOXP3 is an X-linked prostate tumor suppressor in the male. Because the male has only one X chromosome, our data represent a paradigm of "single genetic hit" inactivation-mediated carcinogenesis.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Cells, Cultured
  • Chromosomes, Human, X*
  • Forkhead Transcription Factors / deficiency
  • Forkhead Transcription Factors / genetics*
  • Forkhead Transcription Factors / metabolism
  • Gene Expression Profiling
  • Gene Expression Regulation, Neoplastic*
  • Gene Silencing*
  • Humans
  • Male
  • Mice
  • Mice, Knockout
  • Mutation*
  • Prostatic Hyperplasia / genetics
  • Prostatic Intraepithelial Neoplasia / genetics
  • Prostatic Neoplasms / genetics*
  • Prostatic Neoplasms / metabolism
  • Prostatic Neoplasms / pathology
  • Proto-Oncogene Proteins c-myc / genetics
  • RNA Interference
  • Time Factors
  • Transcription, Genetic
  • Transduction, Genetic

Substances

  • FOXP3 protein, human
  • Forkhead Transcription Factors
  • Foxp3 protein, mouse
  • MYC protein, human
  • Proto-Oncogene Proteins c-myc