Combined MYC activation and Pten loss are sufficient to create genomic instability and lethal metastatic prostate cancer

Gretchen K. Hubbard, Laura N. Mutton, May Khalili, Ryan P. McMullin, Jessica L. Hicks, Daniella Bianchi-Frias, Lucas A. Horn, Ibrahim Kulac, Michael S. Moubarek, Peter S. Nelson, S Yegnasubramanian, Angelo Michael Demarzo, Charles J. Bieberich

Research output: Contribution to journalArticle

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 j PtenFl/Fl) failed to progress beyond prostatic intraepithelial neoplasia and did not harbor genomic CNAs. By contrast, mice with both alterations (Hoxb13-MYC j Hoxb13-Cre j PtenFl/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.

Original languageEnglish (US)
Pages (from-to)283-292
Number of pages10
JournalCancer Research
Volume76
Issue number2
DOIs
StatePublished - Jan 15 2016

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Genomic Instability
Prostatic Neoplasms
Neoplasm Metastasis
Adenocarcinoma
Prostate
Epithelial Cells
Prostatic Intraepithelial Neoplasia
Telomere Shortening
Chromosome Deletion
Penetrance
Genome
Mortality
Neoplasms

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Hubbard, G. K., Mutton, L. N., Khalili, M., McMullin, R. P., Hicks, J. L., Bianchi-Frias, D., ... Bieberich, C. J. (2016). Combined MYC activation and Pten loss are sufficient to create genomic instability and lethal metastatic prostate cancer. Cancer Research, 76(2), 283-292. https://doi.org/10.1158/0008-5472.CAN-14-3280

Combined MYC activation and Pten loss are sufficient to create genomic instability and lethal metastatic prostate cancer. / Hubbard, Gretchen K.; Mutton, Laura N.; Khalili, May; McMullin, Ryan P.; Hicks, Jessica L.; Bianchi-Frias, Daniella; Horn, Lucas A.; Kulac, Ibrahim; Moubarek, Michael S.; Nelson, Peter S.; Yegnasubramanian, S; Demarzo, Angelo Michael; Bieberich, Charles J.

In: Cancer Research, Vol. 76, No. 2, 15.01.2016, p. 283-292.

Research output: Contribution to journalArticle

Hubbard, GK, Mutton, LN, Khalili, M, McMullin, RP, Hicks, JL, Bianchi-Frias, D, Horn, LA, Kulac, I, Moubarek, MS, Nelson, PS, Yegnasubramanian, S, Demarzo, AM & Bieberich, CJ 2016, 'Combined MYC activation and Pten loss are sufficient to create genomic instability and lethal metastatic prostate cancer', Cancer Research, vol. 76, no. 2, pp. 283-292. https://doi.org/10.1158/0008-5472.CAN-14-3280
Hubbard, Gretchen K. ; Mutton, Laura N. ; Khalili, May ; McMullin, Ryan P. ; Hicks, Jessica L. ; Bianchi-Frias, Daniella ; Horn, Lucas A. ; Kulac, Ibrahim ; Moubarek, Michael S. ; Nelson, Peter S. ; Yegnasubramanian, S ; Demarzo, Angelo Michael ; Bieberich, Charles J. / Combined MYC activation and Pten loss are sufficient to create genomic instability and lethal metastatic prostate cancer. In: Cancer Research. 2016 ; Vol. 76, No. 2. pp. 283-292.
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