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A mouse model of heterogeneous, c-MYC-initiated prostate cancer with loss of Pten and p53

Oncogene volume 31, pages 322–332 (2012)Cite this article

Abstract

Human tumors are heterogeneous and evolve through a dynamic process of genetic mutation and selection. During this process, the effects of a specific mutation on the incipient cancer cell may dictate the nature of subsequent mutations that can be tolerated or selected for, affecting the rate at which subsequent mutations occur. Here we have used a new mouse model of prostate cancer that recapitulates several salient features of the human disease to examine the relative rates in which the remaining wild-type alleles of Pten and p53 tumor suppressor genes are lost. In this model, focal overexpression of c-MYC in a few prostate luminal epithelial cells provokes a mild proliferative response. In the context of compound Pten/p53 heterozygosity, c-MYC-initiated cells progress to prostatic intraepithelial neoplasia (mPIN) and adenocarcinoma lesions with marked heterogeneity within the same prostate glands. Using laser capture microdissection and gene copy number analyses, we found that the frequency of Pten loss was significantly higher than that of p53 loss in mPIN but not invasive carcinoma lesions. c-MYC overexpression, unlike Pten loss, did not activate the p53 pathway in transgenic mouse prostate cells, explaining the lack of selective pressure to lose p53 in the c-MYC-overexpressing cells. This model of heterogeneous prostate cancer based on alterations in genes relevant to the human disease may be useful for understanding pathogenesis of the disease and testing new therapeutic agents.

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Abbreviations

PIN:

prostatic intraepithelial neoplasia

LCM:

laser-captured microdissection

BHQ:

black hole quencher

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Acknowledgements

We would like to thank the members of the Abdulkadir Lab for helpful discussions. This work was supported by Grants CA094858 and CA123484 (SAA) from the National Cancer Institute of the National Institutes of Health.

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Authors and Affiliations

  1. Department of Pathology, Vanderbilt University Medical Center, Nashville, TN, USA

    J Kim, M Roh, I Doubinskaia, G N Algarroba & S A Abdulkadir

  2. College of Agricultural and Life Sciences, University of Florida at Gainesville, Gainesville, FL, USA

    G N Algarroba

  3. Department of Pathology, University of Alabama at Birmingham, Birmingham, AL, USA

    I-E A Eltoum

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  1. J Kim
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Correspondence to S A Abdulkadir.

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Kim, J., Roh, M., Doubinskaia, I. et al. A mouse model of heterogeneous, c-MYC-initiated prostate cancer with loss of Pten and p53. Oncogene 31, 322–332 (2012). https://doi.org/10.1038/onc.2011.236

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