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Knockin of SV40 Tag oncogene in a mouse adenocarcinoma of the prostate model demonstrates advantageous features over the transgenic model

Oncogene volume 24, pages 1510–1524 (2005)Cite this article

Abstract

Prostate cancer (CaP) is the most common cancer in adult men in North America. Since there is no naturally occurring prostate cancer in the mouse, preclinical studies stipulate for the establishment of a genetically manipulated mouse CaP model with features close to the human situation. In view of the limitations of transgenic technique-derived CaP models, herein we report the first application of knockin technology to establish a new mouse adenocarcinoma prostate model (PSP-KIMAP) by targeting of SV40 Tag to a prostate tissue-specific gene, PSP94 (prostate secretory protein of 94 amino acids). In order to demonstrate its novelty, we compared KIMAP to a PSP94 gene-directed transgenic mouse adenocarcinoma of the prostate (PSP-TGMAP) model. The CaP development of the PSP-KIMAP mice started almost immediately after puberty at 10 weeks of age from mouse prostatic intraepithelial neoplasia (mPIN) with microinvasion to well-differentiated CaP, and demonstrated a close-to-human kinetics of prolonged tumor growth and a predominance of well and moderately differentiated tumors. The invasive nature of KIMAP model was demonstrated by multitissue metastases (lymph node, lung and liver etc) and also by immunohistochemical study of multiple invasive prostate tumor markers. PSP-KIMAP model is responsive to androgen deprivation (castration). The knockin technology in our KIMAP model demonstrates highly predictive CaP development procedures and many advantageous features, which the traditional transgenic technique-derived CaP models could not reach for both basic and clinical studies. These features include the high stability of both phenotype and genotype, highly synchronous prostate cancer development, high and precise prostate tissue targeting and with no founder line variation. The differences between the two CaP models were attributed to the introduction of a single endogenous knockin mutation, resulting in a CaP model self-regulated and controlled by a prostate gene promoter/enhancer of PSP94.

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Abbreviations

PSP94:

β-microseminoprotein, prostate secretory protein of 94 amino acids

CaP:

prostate cancer

GE:

genetically engineered

ES cell:

embryonic stem cell

PSP-TGMAP:

PSP94-transgenic mouse adenocarcinoma of the prostate

PSP-KIMAP:

PSP94-knockin mouse adenocarcinoma of the prostate

DLP:

dorsolateral prostate

VP:

ventral prostate

AP/CG:

anterior lobe, or coagulation gland

mPIN:

mouse prostatic intraepithelial neoplasia

SV40 Tag:

simian virus T antigen

AR:

androgen receptor

NE:

neuroendocrine

NPT:

nonprostate targeting

RT–PCR:

reverse transcriptase–polymerase chain reaction

IHC:

immunohistochemistry

H&E:

hematoxylin and eosin staining

PCNA:

proliferating cell nuclear antigen

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Acknowledgements

This work was supported by grants from the Canadian Institute of Health Research (UOP-63722, MT-15390), The Kidney Foundation of Canada, The Prostate Cancer Research Foundation of Canada, and from Procyon Biopharma Inc. Montreal, Quebec, Canada. JWX is a recipient of CIHR University-Industry Scientist salary award.

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Author notes

  1. Wenming Duan and Manal Y Gabril: These authors contributed equally to this work

Authors and Affiliations

  1. Department of Surgery, University of Western Ontario, Ontario, London, Canada

    Wenming Duan, Manal Y Gabril & Jim W Xuan

  2. Department of Pathology, University of Western Ontario, Ontario, London, Canada

    Manal Y Gabril, Madeleine Moussa & Jim W Xuan

  3. Department of Anatomy, The Chinese University of Hong Kong, Hong Kong, China

    Franky L Chan

  4. Department of Urology, Nagasaki University School of Medicine, Nagasaki, Japan

    Hideki Sakai

  5. Department of Physiology, University of Connecticut, Farmington, CT, USA

    Guohua Fong

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  1. Wenming Duan
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Correspondence to Jim W Xuan.

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Supplementary information accompanies the paper on Oncogene Website (http://www.nature.com/onc).

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Duan, W., Gabril, M., Moussa, M. et al. Knockin of SV40 Tag oncogene in a mouse adenocarcinoma of the prostate model demonstrates advantageous features over the transgenic model. Oncogene 24, 1510–1524 (2005). https://doi.org/10.1038/sj.onc.1208229

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