title: Combined MYC Activation and Pten Loss Are Sufficient to Create Genomic Instability and Lethal Metastatic Prostate Cancer.
abstract: 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 PTEN, and amplification of 8q24, harboring MYC, 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 MYC overexpression or targeted Pten 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 Pten loss with focal MYC overexpression in a small fraction of prostatic epithelial cells exhibits cooperativity in GEMMs, additional targeted Tp53 disruption was required for formation of metastases. We hypothesized that driving combined MYC overexpression and Pten loss using recently characterized Hoxb13 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 MYC activation alone (Hoxb13-MYC) or Pten loss alone (Hoxb13-Cre∣Pten(Fl/Fl)) failed to progress beyond prostatic intraepithelial neoplasia and did not harbor genomic CNAs. By contrast, mice with both alterations (Hoxb13-MYC∣Hoxb13-Cre∣Pten(Fl/Fl), hereafter, BMPC mice) developed lethal adenocarcinoma with distant metastases and widespread genome CNAs that were independent of forced disruption of Tp53 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 MYC activation and Pten loss driven by the Hoxb13 regulatory locus synergize to induce genomic instability and aggressive prostate cancer that phenocopies the human disease at the histologic and genomic levels.
authors.affiliation: Department of Biological Sciences, University of Maryland, Baltimore County, Baltimore, Maryland. Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, Maryland.
authors.forename: Gretchen K
authors.initials: GK
authors.lastname: Hubbard
authors.affiliation: Department of Biological Sciences, University of Maryland, Baltimore County, Baltimore, Maryland.
authors.forename: Laura N
authors.initials: LN
authors.lastname: Mutton
authors.affiliation: Department of Biological Sciences, University of Maryland, Baltimore County, Baltimore, Maryland.
authors.forename: May
authors.initials: M
authors.lastname: Khalili
authors.affiliation: Department of Biological Sciences, University of Maryland, Baltimore County, Baltimore, Maryland.
authors.forename: Ryan P
authors.initials: RP
authors.lastname: McMullin
authors.affiliation: Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, Maryland.
authors.forename: Jessica L
authors.initials: JL
authors.lastname: Hicks
authors.affiliation: Divisions of Human Biology and Clinical Research, Fred Hutchinson Cancer Research Center, Seattle, Washington.
authors.forename: Daniella
authors.initials: D
authors.lastname: Bianchi-Frias
authors.affiliation: Department of Biological Sciences, University of Maryland, Baltimore County, Baltimore, Maryland.
authors.forename: Lucas A
authors.initials: LA
authors.lastname: Horn
authors.affiliation: Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, Maryland.
authors.forename: Ibrahim
authors.initials: I
authors.lastname: Kulac
authors.affiliation: Department of Biological Sciences, University of Maryland, Baltimore County, Baltimore, Maryland.
authors.forename: Michael S
authors.initials: MS
authors.lastname: Moubarek
authors.affiliation: Divisions of Human Biology and Clinical Research, Fred Hutchinson Cancer Research Center, Seattle, Washington.
authors.forename: Peter S
authors.initials: PS
authors.lastname: Nelson
authors.affiliation: Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland.
authors.forename: Srinivasan
authors.initials: S
authors.lastname: Yegnasubramanian
authors.affiliation: Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, Maryland. Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland. The Brady Urological Research Institute, Johns Hopkins University School of Medicine, Baltimore, Maryland.
authors.forename: Angelo M
authors.initials: AM
authors.lastname: De Marzo
authors.affiliation: Department of Biological Sciences, University of Maryland, Baltimore County, Baltimore, Maryland. bieberic@umbc.edu.
authors.forename: Charles J
authors.initials: CJ
authors.lastname: Bieberich
mesh_terms: D000818:Animals; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D042822:Genomic Instability; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D051059:PTEN Phosphohydrolase / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism; D011471:Prostatic Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D064129:Prostatic Neoplasms, Castration-Resistant / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics* / Q000378:metabolism
chemical_list: C484414:HOXB13 protein, human; D018398:Homeodomain Proteins; C489427:MYC protein, human; D016271:Proto-Oncogene Proteins c-myc; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human