MYC cooperates with AKT in prostate tumorigenesis and alters sensitivity to mTOR inhibitors Journal Article
| Authors: | Clegg, N. J.; Couto, S. S.; Wongvipat, J.; Hieronymus, H.; Carver, B. S.; Taylor, B. S.; Ellwood-Yen, K.; Gerald, W. L.; Sander, C.; Sawyers, C. L. |
| Article Title: | MYC cooperates with AKT in prostate tumorigenesis and alters sensitivity to mTOR inhibitors |
| 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. © 2011 Clegg et al. |
| Keywords: | protein kinase b; human tissue; protein expression; gene mutation; placebo; cancer growth; nonhuman; t lymphocyte; mouse; animal tissue; mus; gene amplification; gene expression; cell infiltration; animal experiment; animal model; enzyme activation; chemosensitivity; phosphatidylinositol 3 kinase; b lymphocyte; carcinogenesis; cancer resistance; myc protein; prostate tumor; prostatic intraepithelial neoplasia; macrophage; everolimus; oncogene myc |
| Journal Title: | PLoS ONE |
| Volume: | 6 |
| Issue: | 3 |
| ISSN: | 1932-6203 |
| Publisher: | Public Library of Science |
| Date Published: | 2011-03-04 |
| Start Page: | e17449 |
| Language: | English |
| DOI: | 10.1371/journal.pone.0017449 |
| PROVIDER: | scopus |
| PMCID: | PMC3048873 |
| PUBMED: | 21394210 |
| DOI/URL: | |
| Notes: | --- - "Export Date: 23 June 2011" - "Art. No.: e17449" - "Source: Scopus" |
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