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

Date:	January 2 2026
PMID:	41081599
Category:	N/A
Authors:	Michael Rubenstein, Apurv Rege, Gretchen Hubbard, Danielle Cannady, Shreya Agarwal, Kevin Chen, Alex Estrada, Carolina Gomes-Alexandre, Jessica Hicks, Tracy Jones, Qizhi Zheng, Srinivasan Yegnasubramanian, Charles J Bieberich, Angelo M De Marzo
DOI:	10.1158/1541-7786.MCR-24-1206

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 lesions. In this study, we performed transcriptomic profiling of PIN lesions from each of the three genotypes. Whereas 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 is required for cell proliferation. Whereas 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 lesions and early carcinomas. Some MYC targets were increased only after Pten loss, indicating Pten loss increases MYC activity.

Implications: 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. These results provide further support for the therapeutic targeting of translation in prostate cancer.

---

Acknowledgements:

The content of this article is solely the responsibility of the authors and does not necessarily represent the official views of the National Cancer Institute, or the National Institute of Health.

The Translational and Basic Science Research in Early Lesions (TBEL) Research Consortia is supported and funded by grants from the National Cancer Institute and the National Institutes of Health under the following award numbers:

Project Number:	Awardee Organization
U54CA274374	Fred Hutchinson Cancer Center
U54CA274375	Houston Methodist Research Institute
U54CA274370	Johns Hopkins University
U54CA274371	UT MD Anderson Cancer Center
U54CA274367	Vanderbilt University Medical Center