Molecular Characterization of the G gamma-Globin-TagTransgenic Mouse Model of Hormone Refractory Prostate Cancer: Comparison to Human Prostate Cancer

作者：Calvo Alfonso; Perez Stable Carlos; Segura Victor; Catena Raul; Guruceaga Elizabeth; Nguewa Paul; Blanco David; Parada Luis; Reiner Teresita; Green Jeffrey E^*

来源：Prostate, 2010, 70(6): 630-645.

DOI：10.1002/pros.21097

• prostate cancer
• transgenic mouse
• gene expression
• microarrays
• stathmin-1

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 (G gamma-globin-Tag) transgenic mouse model for PrCa compared to normal mouse prostate tissue. Gene expression patterns found in G gamma-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. G gamma-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 G gamma-globin-Tag tumors, which displayed similarities to alterations in human PrCa. Changes in the expression of genes involved in DNA replication and repair (Rb, p53, Myc, PCNA, DNMT3A) and growth factor signaling pathways (TGF beta 2, ERK1/2, NRas, and Notch) are deregulated in the G gamma-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 G gamma-globin-Tag carcinogenesis, including SP, NF-Y, CREB, Elk, and E2F. Novel genes related to microtubule regulation were also identified in G gamma-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 G gamma-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 G gamma-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 G gamma-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. Prostate 70: 630-645, 2010.Published 2010 Wiley-Liss, Inc.(dagger)

• 出版日期2010-5-1