Abstract 3043: MYC activation and PTEN loss synergistically activate proliferation in a mouse model of lethal prostate cancer
Authors: Rubenstein Michael , Jones Tracy , Hicks Jessica , Rege Apurv , Zheng Qizhi , Gomes-Alexandre Carolina , Hubbard Gretchen , Yegnasubramanian Srinivasan , Bieberich Charles , DeMarzo Angelo 
Published: March 2024

Abstract
Prostate cancer kills 30,000 men per year in the U.S. Yet, of all primary prostate cancers, only a relatively small percentage are aggressive and have the potential to become life threatening. In terms of genomic copy number alterations, concurrent amplification of MYC and loss of tumor suppressor PTEN is the strongest predictor of prostate cancer specific mortality. We have previously shown, in a novel mouse model, that combined MYC overexpression and Pten loss results in the development of precursor lesions (PIN) that lead to aggressive metastatic prostatic adenocarcinoma, yet overexpression of MYC alone or Pten loss alone result only in precursor lesion development. Here, we performed genome wide transcriptome analysis using bulk RNA seq to obtain clues regarding the synergy between MYC overexpression and Pten loss. Prostates harboring PIN lesion were dissected from mice engineered to have MYC activation alone, Pten loss alone, and the combination thereof (BMPC mice), as well as invasive primary adenocarcinomas and metastatic lesions from BMPC mice. Principal Components Analysis (PCA) analysis separated the lesions into highly distinct groups. Genes contributing the most to the first principal component were related to inflammation and cell proliferation/cell cycle progression by functional annotation. The proliferation-related genes were increased somewhat by MYC overexpression alone, were not increased Pten loss, and were more consistently increased by combined MYC overexpression and Pten loss in BMPC. Strikingly, mice with combined MYC overexpression and Pten loss showed approximately 2-4 fold higher Ki67 proliferation index than mice with MYC activation alone. PIN lesions driven by MYC overexpression or PTEN loss alone were characterized by Gene Set Enrichment Analysis (GSEA). Among the pathways with the highest negative enrichment scores in PIN samples with PTEN loss were those that generally describe ribosome biogenesis and translation. PIN lesions with Pten loss showed lower hybridization signals for the 45S rRNA, which was increased by MYC alone and somewhat more in BMPC PIN lesions. Our results demonstrate that combined activation of MYC and Pten loss drive increased cell proliferation beyond that seen with either gene alteration alone. These findings suggest that a key part of the molecular mechanisms by which MYC and PTEN alterations may synergize to drive aggressive prostate cancer is related to increased tumor cell proliferation. Surprisingly, we uncovered the novel finding that Pten loss, in the absence of MYC overexpression, is associated with decreased expression of genes coding for proteins that mediate translation, as well as decreased 45S pre-rRNA. Since ribosome biogenesis is a key driver of cell proliferation, it is likely that loss of both copies of PTEN alone, in the absence of MYC overexpression, would be selected against in early lesions in prostate cancer.
Citation Format: Michael Rubenstein, Tracy Jones, Jessica Hicks, Apurv Rege, Qizhi Zheng, Carolina Gomes-Alexandre, Gretchen Hubbard, Srinivasan Yegnasubramanian, Charles Bieberich, Angelo DeMarzo. MYC activation and PTEN loss synergistically activate proliferation in a mouse model of lethal prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 3043.