SPOP Mutation Drives Prostate Tumorigenesis In Vivo through Coordinate Regulation of PI3K/mTOR and AR Signaling

Cancer Cell. 2017 Mar 13;31(3):436-451. doi: 10.1016/j.ccell.2017.02.004.


Recurrent point mutations in SPOP define a distinct molecular subclass of prostate cancer. Here, we describe a mouse model showing that mutant SPOP drives prostate tumorigenesis in vivo. Conditional expression of mutant SPOP in the prostate dramatically altered phenotypes in the setting of Pten loss, with early neoplastic lesions (high-grade prostatic intraepithelial neoplasia) with striking nuclear atypia and invasive, poorly differentiated carcinoma. In mouse prostate organoids, mutant SPOP drove increased proliferation and a transcriptional signature consistent with human prostate cancer. Using these models and human prostate cancer samples, we show that SPOP mutation activates both PI3K/mTOR and androgen receptor signaling, effectively uncoupling the normal negative feedback between these two pathways.

Keywords: PI3K/mTOR; SPOP; androgen receptor; cancer genomics; organoids; prostate cancer; proteomics; transgenic mouse model.

MeSH terms

  • Animals
  • Cell Proliferation
  • Humans
  • Male
  • Mice
  • Mutation*
  • Nuclear Proteins / genetics*
  • Nuclear Receptor Coactivator 3 / physiology
  • PTEN Phosphohydrolase / genetics
  • Phosphatidylinositol 3-Kinases / physiology*
  • Prostatic Neoplasms / etiology*
  • Prostatic Neoplasms / genetics
  • Prostatic Neoplasms / pathology
  • Proto-Oncogene Proteins c-ets / physiology
  • Receptors, Androgen / physiology*
  • Repressor Proteins / genetics*
  • Signal Transduction / physiology*
  • TOR Serine-Threonine Kinases / physiology*


  • Nuclear Proteins
  • Proto-Oncogene Proteins c-ets
  • Receptors, Androgen
  • Repressor Proteins
  • SPOP protein, human
  • NCOA3 protein, human
  • Nuclear Receptor Coactivator 3
  • TOR Serine-Threonine Kinases
  • PTEN Phosphohydrolase