GSE129243
LOSS OF THE TUMOR SUPPRESSOR, TP53, ENHANCES THE ANDROGEN RECEPTOR MEDIATED ONCOGENIC TRANSFORMATION AND TUMOR DEVELOPMENT IN THE MOUSE PROSTATE
Androgen signaling is essential for prostate tumorigenesis. The tumor suppressor p53 has been implicated in prostate cancer progression. Recent genome analysis of human prostate cancers demonstrated that both AR gene amplification and TP53 deletion are frequently altered in advanced prostate cancer. However, the biological role of these dual genetic alterations in prostate tumorigenesis is largely unknown. In addition, there are no biologically relevant models that can be used to assess these genetic abnormalities in the prostate.  Here, we report a novel mouse model, in which elevated transgenic AR expression and Trp53 deletion occur simultaneously in mouse prostatic epithelium to mimic what happens in human prostate cancer cells.  These compound mice developed an earlier onset of high-grade prostatic intraepithelial neoplasia and accelerated prostate tumors. Histological analysis showed pathological lesions resembling prostatic sarcomatoid and basaloid carcinomas with massive squamous differentiation in the above compound mice. RNA-sequencing analyses showed a robust enrichment of the signature genes for human prostatic basal cell carcinomas in the above prostate tumors. The Master Regulator Analysis further identified SOX2 as a transcriptional regulator in prostatic basal cell tumors. Elevated expression of SOX2 and its downstream target genes were detected in prostatic tumors of the compound mice. Chromatin immunoprecipitation analyses implicate a co-regulatory role of AR and SOX2 in the expression of prostatic basal cell signature genes. These results demonstrate a novel mechanism underlying elevated AR expression and Trp53 deletion induced prostate cancer cell trans-differentiation, aggressiveness, and progression. Overall design: In search of the molecular basis for the collaborative role of transgenic AR expression and Trp53 deletion in prostate tumorigenesis, we performed RNA-sequencing (RNA-seq) to examine the global transcriptome profiles in the tumor tissue of different genotype mice.