Data from Combined <i>MYC</i> Activation and <i>Pten</i> Loss Are Sufficient to Create Genomic Instability and Lethal Metastatic Prostate Cancer

Abstract

<div>Abstract<p>Genetic instability, a hallmark feature of human cancers including prostatic adenocarcinomas, is considered a driver of metastasis. Somatic copy number alterations (CNA) are found in most aggressive primary human prostate cancers, and the overall number of such changes is increased in metastases. Chromosome 10q23 deletions, encompassing <i>PTEN</i>, and amplification of 8q24, harboring <i>MYC</i>, are frequently observed, and the presence of both together portends a high risk of prostate cancer-specific mortality. In extant genetically engineered mouse prostate cancer models (GEMM), isolated <i>MYC</i> overexpression or targeted <i>Pten</i> loss can each produce early prostate adenocarcinomas, but are not sufficient to induce genetic instability or metastases with high penetrance. Although a previous study showed that combining <i>Pten</i> loss with focal <i>MYC</i> overexpression in a small fraction of prostatic epithelial cells exhibits cooperativity in GEMMs, additional targeted <i>Tp53</i> disruption was required for formation of metastases. We hypothesized that driving combined <i>MYC</i> overexpression and <i>Pten</i> loss using recently characterized <i>Hoxb13</i> transcriptional control elements that are active in prostate luminal epithelial cells would induce the development of genomic instability and aggressive disease with metastatic potential. Neoplastic lesions that developed with either <i>MYC</i> activation alone (<i>Hoxb13-MYC</i>) or <i>Pten</i> loss alone (<i>Hoxb13-Cre</i>∣<i>Pten</i><sup>Fl/Fl</sup>) failed to progress beyond prostatic intraepithelial neoplasia and did not harbor genomic CNAs. By contrast, mice with both alterations (<i>Hoxb13-MYC</i>∣<i>Hoxb13-Cre</i>∣<i>Pten</i><sup>Fl/Fl</sup>, hereafter, BMPC mice) developed lethal adenocarcinoma with distant metastases and widespread genome CNAs that were independent of forced disruption of <i>Tp53</i> and telomere shortening. BMPC cancers lacked neuroendocrine or sarcomatoid differentiation, features uncommon in human disease but common in other models of prostate cancer that metastasize. These data show that combined <i>MYC</i> activation and Pten loss driven by the <i>Hoxb13</i> regulatory locus synergize to induce genomic instability and aggressive prostate cancer that phenocopies the human disease at the histologic and genomic levels. <i>Cancer Res; 76(2); 283–92. ©2015 AACR</i>.</p></div>