Mouse models of prostate cancer development and metastasis through expression of a hepsin transgene
View Patent ↗Transgenic, non-human animal model of cancer, methods of making such animals and methods of using such animals to screen test compounds are provided.
1. A transgenic mouse whose genome comprises a hepsin transgene operably linked to a prostate specific promoter, wherein the hepsin transgene is expressed in prostate epithelial tissue, and wherein the transgenic mouse has a disrupted or disorganized prostate basement membrane.
2. The transgenic mouse of claim 1 , wherein the hepsin transgene is overexpressed in the prostate epithelial tissue.
3. The transgenic mouse of claim 1 , wherein the hepsin transgene is a mouse transgene.
4. The transgenic mouse of claim 1 , wherein the hepsin transgene is a cognate, heterologous hepsin transgene.
5. The transgenic mouse of claim 4 , wherein the hepsin transgene is a human transgene.
6. The transgenic mouse of claim 1 , wherein the prostate specific promoter is a probasin promoter.
7. The transgenic mouse of claim 1 , wherein the mouse further expresses a SV40 large T antigen operably associated with a prostate specific promoter.
8. The transgenic mouse of claim 7 , wherein the prostate specific promoter is a probasin promoter.
9. The transgenic mouse of claim 7 , wherein primary prostate cancer progression or metastasis is increased in the mouse, as compared with a control mouse having the same genetic predisposition, but not expressing the hepsin transgene.
10. The transgenic mouse of claim 9 , wherein the transgenic mouse has increased metastasis to the liver, lung or bone.
11. A method of producing a transgenic mouse suitable for screening agents for use in the detection or treatment of prostate cancer, comprising:
forming a plurality of transgenic mice comprising a diploid genome encoding a hepsin transgene operably linked to a prostate specific promoter;
selecting one of the transgenic mice wherein the hepsin transgene is overexpressed to produce a hepsin polypeptide, and wherein the hepsin polypeptide exhibits tissue-specific expression;
breeding the selected transgenic mouse to a mouse of the same species comprising an SV40 T antigen transagene operably linked to a prostate specific promoter integrated in its genome; and
selecting one of the progeny transgenic mice overexpressing the hepsin transgene in the prostate wherein said progeny transgenic mice have a predisposition for prostate cancer.
12. The method of claim 11 , wherein the hepsin transgene is a mouse transgene.
13. The method of claim 11 , wherein the hepsin transgene is a cognate, heterologous transgene.
14. The method of claim 13 , wherein the hepsin transgene is a human hepsin transgene.
15. A method of screening an agent for use in the detection or treatment of prostate cancer, comprising:
providing a transgenic mouse comprising a diploid genome, having a genetic predisposition for prostate cancer and encoding a hepsin transgene operably linked to a prostate specific promoter and an SV40 T antigen transgene operably linked to a prostate specific promoter, wherein the hepsin transgene is overexpressed;
contacting the transgenic mouse with the test compound at a dosage of from about 1 ng/kg to about 10 mg/kg; and
examining the contacted transgenic mouse to determine whether the test compound affects tumor development, progression or metastasis.
16. The method of claim 15 , wherein the dosage of the test compound is from about 10 μg/kg to about 1 mg/kg.
17. The method of claim 15 , wherein the test compound does not inhibit hepsin.
18. The method of claim 15 , wherein the test compound decreases metastasis to the liver, lung or bone.
19. The method of claim 18 , further comprising determining whether the test compound inhibits hepsin.