Prostate cancer in a transgenic mouse.

Abstract

Progress toward understanding the biology of prostate cancer has been slow due to the few animal research models available to study the spectrum of this uniquely human disease. To develop an animal model for prostate cancer, several lines of transgenic mice were generated by using the prostate-specific rat probasin promoter to drive expression of the simian virus 40 large tumor antigencoding region. Mice expressing high levels of the transgene display progressive forms of prostatic disease that histologically resemble human prostate cancer, ranging from mild intraepithelial hyperplasia to large multinodular malignant neoplasia. Prostate tumors have been detected specirically in the prostate as early as 10 weeks ofage. Immunohistochemical analysis of tumor tissue has demonstrated that dorsolateral prostate-specific secretory proteins were confined to welldifferentiated ductal epithelial cells adjacent to, or within, the poorly differentiated tumor mass. Prostate tumors in the mice also display elevated levels of nuclear p53 and a decreased heterogeneous pattern of androgen-receptor expression, as observed in advanced human prostate cancer. The establishment of breeding lines of transgenic mice that reproducibly develop prostate cancer provides an animal model system to study the molecular basis of transformation of normal prostatic cells and the factors influencing the progression to metastatic prostate cancer.Prostate cancer will likely claim the lives of 35,000 men in the United States this year alone, and some 200,000 more men will be diagnosed with the disease (1). However, progress toward understanding the biology of prostate cancer and the development of new therapies for this disease has been slowed, in part, by the need for in vivo model systems that adequately reproduce the spectrum of benign, latent, aggressive, and metastatic forms of the human disease.Prostate cancer is a disease quite unique to man. Although naturally occurring prostatic disease has been reported in some canine (2) and rodent (3-5) species, these animals have not provided the appropriate models to adequately study the molecular mechanisms related to the early development and progression of human prostate cancer. To this end, we initiated a research program to establish a transgenic animal model for prostate cancer by using a prostate-specific transgene expression system that has been developed in our laboratories based on the regulatory elements of the rat probasin (rPB)-encoding gene.The rPB gene encodes an androgen-and zinc-regulated protein specific to the dorsolateral epithelium (6-8). Isolation of the rPB gene has facilitated identification of cis-acting androgen-response regions within the 5' flanking region (9). More recently, the ability of the prostate-specific rPB gene promoter to target heterologous genes specifically to the prostate in transgenic mice has been demonstrated (10). InThe publication costs of this article were defrayed in part by page charge payment. This article must therefore be hereby marked "adver...

Prostate targeting: PSP94 gene promoter/enhancer region directed prostate tissue-specific expression in a transgenic mouse prostate cancer model

“…17,18 The PSA promoter region has not yet been used to target prostatic function in transgenic mice. 8 The transgenic adenocarcinoma mouse prostate (TRAMP) [19][20][21] and the LPB-Tag 22,23 models are all based on a prostate-specific gene, rat probasin (rPB), for targeting to the prostate and directing the SV40 Tag (SV40 T and t antigens) expression. The rPB gene as a targeting vector represents a major advance in the establishment of a mouse model for prostate cancer research.…”

“…24 Recently, an osteocalcin promoter was used in a novel strategy for cotargeting both tumor epithelial and bone stromal cells in gene therapy of androgen-independent CaP bone metastasis. 25,26 Current gene therapy clinical trials of prostate cancer utilize a combination of the only two available targeting vector genes with both the rat probasin promoter sequence and human PSA promoter sequence 13,20,27 without the benefit of prior testing in an appropriate transgenic animal model. 8,28,29 Both vector genes of rat PB and human PSA have been challenged by the fact that neither a human counterpart of the rPB gene nor rodent counterpart of the human PSA gene has been clearly identified due to interspecies divergence.…”

The impact of bcl-2 expression and bax deficiency on prostate homeostasis in vivo

“…The most extensively studied transgenic model involves the targeting of transgene expression using the probasin promoter (Greenberg et al, 1995;Gingrich et al, 1996Gingrich et al, , 1997. We used the probasin promoter to target expression of a human bcl-2 transgene speci®-cally to the prostate in order to assess its impact on conferring resistance to androgen withdrawal in prostatic glandular epithelial cells in vivo.…”

Conditional activation of FGFR1 in the prostate epithelium induces angiogenesis with concomitant differential regulation of Ang-1 and Ang-2

“…These models are particularly well suited to the examination of the earliest events during tumor progression, such as angiogenesis, and have proven their utility in examining the effects of specific pathway alterations in vivo. Although the TRansgenic Adenocarcinoma of the Mouse Prostate (TRAMP) model (Greenberg et al, 1995) recapitulates many of the changes in the FGF axis observed clinically, such as exhibiting higher expression of FGFR1 in advanced tumors and in portions of tumor vasculature (Huss et al, 2003), and increased expression of both FGF1 (Foster et al, 1999) and FGF2 (Huss et al, 2003) during tumor progression, the TRAMP model does not allow specific regulation of FGFR1. Therefore, to better define the role of FGFR1 in the prostate, mice were generated that express a constitutively active FGFR1 (caFGFR1) under the control of the probasin promoter.…”