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Review
. 2019 Oct 1;9(10):2079-2102.
eCollection 2019.

From genomics to functions: preclinical mouse models for understanding oncogenic pathways in prostate cancer

Chuan Yu  1 , Kevin Hu  1 , Daniel Nguyen  1 , Zhu A Wang  1
Affiliations
Review

From genomics to functions: preclinical mouse models for understanding oncogenic pathways in prostate cancer

Chuan Yu et al. Am J Cancer Res. .

Abstract

Next-generation sequencing has revealed numerous genomic alterations that induce aberrant signaling activities in prostate cancer (PCa). Among them are pathways affecting multiple cancer types, including the PI3K/AKT/mTOR, p53, Rb, Ras/Raf/MAPK, Myc, FGF, and Wnt signaling pathways, as well as ones that are prominent in PCa, including alterations in genes of AR signaling, the ETS family, NKX3.1, and SPOP. Cross talk among the oncogenic pathways can confer PCa resistance to therapy, particularly in advanced tumors, which are castration-resistant or show neuroendocrine features. Various experimental models, such as cancer cell lines, animal models, and patient-derived xenografts and organoids have been utilized to dissect PCa progression mechanisms. Here, we review the current preclinical mouse models for studying the most commonly altered pathways in PCa, with an emphasis on their interplays. We highlight the power of genetically engineered mouse models (GEMMs) in translating genomic discoveries into understanding of the functions of these oncogenic events in vivo. Developing and analyzing PCa mouse models will undoubtedly continue to offer new insights into tumor biology and guide novel rationalized therapy.

Keywords: AR; ETS; PI3K; Prostate; Wnt; cancer progression; castration-resistance; mouse models; neuroendocrine; p53.

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Conflict of interest statement

None.

Figures

Figure 1
Figure 1
Overview of PCa stages, treatment options, and molecular alterations. Cancer progression in the prostate undergoes different stages from hyperplasia to metastatic tumor. Timing and the temporary effect on the tumor volume are shown for different treatment options at various stages. Genomics studies have revealed major molecular alterations in PCa, shown in their likely order during cancer progression. Color code indicates whether the alteration is loss-of-function or gain-of-function.
Figure 2
Figure 2
Mouse models used to study the PI3K/AKT/mTOR axis in PCa. Major components of the PI3K/AKT/mTOR pathway and their molecular signaling relationships are shown. Pioneer papers that described the GEM models of the individual components or their interactions are listed.
Figure 3
Figure 3
Using GEMMs to study pathway interactions in PCa progression. Diagram summarizes pathway interactions shown to promote PCa progression by studying GEMMs. The PI3K pathway activation has been the most extensively modeled event in PCa GEMMs and usually serves as a baseline model. Cooperation of PI3K pathway with other pathways is required for PCa to overcome various barriers and checkpoints to progress. Each line connecting two pathways indicates that at least one GEMM has been used to establish a functional correlation of the two pathways, through analyzing either phenotypes of double mutant mice or pathway activities in single mutant mice. Pathway interactions revealed by cancer cell line and xenograft studies are not drawn.
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