The Development and Characterization of a Transgenic Mouse Model Over-Expressing a Truncated TGF(Beta) Type II Receptor in the Prostate
Abstract
Early reports have noted increased expression of TGF Beta1 and loss of TGF Beta type I and type II (TBetaR11) expression with increasing prostate cancer grade. We have generated mice (MT-DNllR) that express a metallothionein promoter driven truncated TBetaR11 which results in a dominant negative mutant that blocks the TGFBeta pathway in the prostate. Two founder lines (MTR4 & MTR27H) revealed focal regions of low grade PIN, which progress to high grade PIN. Aged mice showed significant histological changes including the development of cribiform and invasive cancer (unpublished data). The MT-DNllR mice show histopathologic changes mimicking those observed in human prostate cancer. Since TGFBeta is negatively regulated by androgens, and has been implicated as a mediator of castration-induced cell death in the prostate, we examined the MTR4 and MTR27H mice to determine the effects of loss of TGFBeta signaling in the regressing prostate. MTR4 and MTR27H mice were castrated and maintained on zinc sulfate in the drinking water. Prostates were collected, weighed and examined histologically, and immunostaining for Proliferating Nuclear Cell Antigen (PC NA) was performed. In non-transgenic mice the anterior prostate (AP), dorsolateral prostate (DLP) and ventral prostate (VP) regressed to 13% (AP), 18% (DLP) and 11% (VP) of sham operated controls (100%) by 35 days post-castration. The histology associated with these tissues was consistent with that expected after androgen withdrawal and no positive immunostaining for PCNA was observed. In contrast, the prostates from 35 day post-castration MTR4 and MTR27H mice had regressed to: AP 30% and 34%, DLP 81% and 57% and VP 50% and 33% respectively.
Document Details
- Document Type
- Technical Report
- Publication Date
- Jul 01, 2000
- Accession Number
- ADA385552
Entities
People
- H. L. Moses
- R. A. Serra
- S. Kasper
- S. Shappell
- Tania Thomas
Organizations
- Vanderbilt University Medical Center