MYC cooperates with AKT in prostate tumorigenesis and alters sensitivity to mTOR inhibitors. Academic Article uri icon

Overview

abstract

  • MYC and phosphoinositide 3-kinase (PI3K)-pathway deregulation are common in human prostate cancer. Through examination of 194 human prostate tumors, we observed statistically significant co-occurrence of MYC amplification and PI3K-pathway alteration, raising the possibility that these two lesions cooperate in prostate cancer progression. To investigate this, we generated bigenic mice in which both activated human AKT1 and human MYC are expressed in the prostate (MPAKT/Hi-MYC model). In contrast to mice expressing AKT1 alone (MPAKT model) or MYC alone (Hi-MYC model), the bigenic phenotype demonstrates accelerated progression of mouse prostate intraepithelial neoplasia (mPIN) to microinvasive disease with disruption of basement membrane, significant stromal remodeling and infiltration of macrophages, B- and T-lymphocytes, similar to inflammation observed in human prostate tumors. In contrast to the reversibility of mPIN lesions in young MPAKT mice after treatment with mTOR inhibitors, Hi-MYC and bigenic MPAKT/Hi-MYC mice were resistant. Additionally, older MPAKT mice showed reduced sensitivity to mTOR inhibition, suggesting that additional genetic events may dampen mTOR dependence. Since increased MYC expression is an early feature of many human prostate cancers, these data have implications for treatment of human prostate cancers with PI3K-pathway alterations using mTOR inhibitors.

publication date

  • March 4, 2011

Research

keywords

  • Precancerous Conditions
  • Prostatic Neoplasms
  • Protein Kinase Inhibitors
  • Proto-Oncogene Proteins c-akt
  • Proto-Oncogene Proteins c-myc
  • TOR Serine-Threonine Kinases

Identity

PubMed Central ID

  • PMC3048873

Scopus Document Identifier

  • 79952341078

Digital Object Identifier (DOI)

  • 10.1371/journal.pone.0017449

PubMed ID

  • 21394210

Additional Document Info

volume

  • 6

issue

  • 3