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