Combined MYC Activation and PTEN Loss Drives Molecular Features of Aggressive Preinvasive Lesions in Mouse Prostate

Abstract

Prostate cancer ranges from indolent to rapidly progressive. An elevated cell proliferation index portends poor outcomes, yet the molecular alterations essential for increased cell proliferation remain ill-defined. Gain of MYC combined with biallelic PTEN loss predicts prostate cancer mortality. Prior studies have shown that combined MYC overexpression and Pten loss, driven by the Hoxb13 locus, results in prostatic intraepithelial neoplastic (PIN) lesions that progress to metastatic disease (BMPC mice). Yet, single gene alterations in these mice result only in PIN. Herein, we performed transcriptomic profiling of PIN lesions from each of the 3 genotypes. While MYC alone resulted in increases in genes related to cell cycle regulation/cell division, combined MYC and Pten loss led to a further and more consistent increase, and a synergistic cell cycle progression. Increased ribosome biogenesis/translation are required for cell proliferation. While MYC alone increased 45S rRNA, and most components of the translation machinery, these were more strongly induced in BMPC mice. Surprisingly, Pten loss alone resulted in a downregulation of translation machinery genes, which could explain the absence of biallelic PTEN loss in human PIN and early carcinomas. Some MYC targets were increased only after Pten loss, indicating Pten loss increases MYC activity. Implications: These findings are that increased cell cycle and translational machinery gene induction may explain the synergy between MYC and PTEN loss for increasing prostate cancer cell proliferation and disease aggressiveness. Finally, these results provide further support for the therapeutic targeting of translation in prostate cancer.