Molecular characterization of the Ggamma-globin-Tag transgenic mouse model of hormone refractory prostate cancer: comparison to human prostate cancer.
BACKGROUND
Prostate cancer (PrCa) has a high incidence in Western countries and at present, there is no cure for hormone refractory prostate cancer. Transgenic mouse models have proven useful for understanding mechanisms of prostate carcinogenesis. The characterization of genetically modified mouse PrCa models using high-throughput genomic analyses provides important information to guide appropriate experiment applications for such model.


METHODS
We have analyzed the transcriptome of the hormone refractory and highly metastatic Fetal Globin-SV40/T-antigen (Ggamma-globin-Tag) transgenic mouse model for PrCa compared to normal mouse prostate tissue. Gene expression patterns found in Ggamma-globin-Tag mouse prostate tumors were compared with publicly available human localized and metastatic prostate tumors (GEO accession # GSE3325) through hierarchical cluster analysis, Pearson's rank correlation coefficient, and Self Organizing Feature Maps (SOM) analyses.


RESULTS
Ggamma-globin-Tag tumors clustered closely with human metastatic tumors and gene expression patterns had a significant correlation (P < 0.01), unlike human localized primary tumors (P > 0.6). Bioinformatic analyses identified deregulated genetic pathways and networks in Ggamma-globin-Tag tumors, which displayed similarities to alterations in human PrCa. Changes in the expression of genes involved in DNA replication and repair (Rb1, p53, Myc, PCNA, DNMT3A) and growth factor signaling pathways (TGFbeta2, ERK1/2, NRas, and Notch1) are deregulated in the Ggamma-globin-Tag tumors, suggesting their key role in the oncogenic process. Identification of an enrichment of putative binding sites for transcription factors revealed eight transcription factors that may be important in Ggamma-globin-Tag carcinogenesis, including SP1, NF-Y, CREB, Elk1, and E2F. Novel genes related to microtubule regulation were also identified in Ggamma-globin-Tag tumors as potentially important candidate targets for PrCa. Overexpression of stathmin-1, whose expression was increased in human metastatic prostate tumors, was validated in Ggamma-globin-Tag tumors by immunohistochemistry. This protein belongs to the SV40/T-antigen cancer signature identified in previous studies in prostate, breast, and lung cancer mouse models.


CONCLUSIONS
Our results show that the Ggamma-globin-Tag model for hormone refractory PrCa shares important features with aggressive, metastatic human PrCa. Given the role of stathmin-1 in the destabilization of microtubles and taxane resistance, the Ggamma-globin-Tag model and other SV40/T-antigen driven transgenic models may be useful for testing potential therapies directed at stathmin-1 in human prostate tumors.
Calvo
Alfonso
A
Division of Oncology, Department of Histology and Pathology, Center for Applied Medical Research, University of Navarra, Pamplona, Spain.
Perez-Stable
Carlos
C
Segura
Victor
V
Catena
Raúl
R
Guruceaga
Elizabeth
E
Nguewa
Paul
P
Blanco
David
D
Parada
Luis
L
Reiner
Teresita
T
Green
Jeffrey E
JE
D000818:Animals; D000957:Antigens, Viral, Tumor / Q000235:genetics*; D016000:Cluster Analysis; D019295:Computational Biology; D004195:Disease Models, Animal; D020869:Gene Expression Profiling; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D011471:Prostatic Neoplasms / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics; D050777:Stathmin / Q000235:genetics / Q000378:metabolism; D055545:gamma-Globins / Q000235:genetics*
D000957:Antigens, Viral, Tumor; C493995:STMN1 protein, human; D050777:Stathmin; C493994:Stmn1 protein, mouse; D055545:gamma-Globins