Genetically Engineered Mouse Models of Prostate Cancer in the Postgenomic Era

Abstract

Recent genomic sequencing analyses have unveiled the spectrum of genomic alterations that occur in primary and advanced prostate cancer, raising the question of whether the corresponding genes are functionally relevant for prostate tumorigenesis, and whether such functions are associated with particular disease stages. In this review, we describe genetically engineered mouse models (GEMMs) of prostate cancer, focusing on those that model genomic alterations known to occur in human prostate cancer. We consider whether the phenotypes of GEMMs based on gain or loss of function of the relevant genes provide reliable counterparts to study the predicted consequences of the corresponding genomic alterations as occur in human prostate cancer, and we discuss exceptions in which the GEMMs do not fully emulate the expected phenotypes. Last, we highlight future directions for the generation of new GEMMs of prostate cancer and consider how we can use GEMMs most effectively to decipher the biological and molecular mechanisms of disease progression, as well as to tackle clinically relevant questions.

Figure 1.

Schematic showing the relationship of genetically engineered mouse model (GEMM) phenotypes to stages of prostate cancer progression and the observed frequencies of genomic alterations on which they are based relative to stages of human prostate cancer. For mouse phenotypes (rows labeled with the mouse symbol), gradients of red are used to denote overexpression or functional activation, and blue is used to denote gene deletion or functional repression. Gray coloring is used to denote where GEMMS do not display phenotypes. Human genomic alterations (rows labeled with the man symbol) show the frequency of occurrence at the specific stages of cancer progression using The Cancer Genome Atlas (TCGA) data set for primary prostate cancer (Cancer Genome Atlas Research 2015), and the SU2C data set (Robinson et al. 2015) for castration-resistant prostate cancer (CRPC) and metastatic disease. Wnt pathway genes include APC, CTNNB1, RSPO2, RNF43, ZNFR3. Ras, Raf genes include KRAS, NRAS, HRAS, BRAF, RAF1. PIN, prostatic intraepithelial neoplasia; AR, androgen receptor; PTEN, phosphatase and tensin homolog.

Figure 2.

Uses of genetically engineered mouse models (GEMMs) to study prostate cancer. Potential areas of interest in which GEMMs can be used to study prostate cancer biology are highlighted inside rectangular boxes. The outer circle highlights the broad fields to which these studies can contribute relevant knowledge.