Dr. Norman Michael Greenberg

Adenocarcinoma of the prostate has become the most common cancer in American men and will be responsible for an estimated 29,900 deaths in 2004, a mortality rate second only to lung cancer. Despite the magnitude of the problem, rapid progress in prostate cancer research has been slow, in part, due to the scarcity of adequate animal model systems that reproduce the spectrum of human prostatic disease. Therefore, the long term objective for my lab is to develop suitable transgenic animal models for prostate cancer to facilitate direct characterization of the molecular and cellular mechanisms governing transformation of the differentiating prostate in vivo and to test novel gene based therapies for prostate cancer.

We have demonstrated that a novel system based on the rat probasin (rPB) gene promoter directs hormonally- and developmentally- regulated expression of heterologous genes specifically to the prostate in transgenic mice. To develop the transgenic adenocarcinoma mouse prostate model (TRAMP) model a PB promoter - SV40 T antigen fusion transgene (PB-Tag) was introduced into the germ line of C57BL/6 inbred mice. The TRAMP mice develop spontaneous progressive autochthonous prostate cancer with complete penetrance that metastasizes to the lymph nodes, lung and bone. The SV40 T antigen oncoprotein was used because it abrogates the functional expression of p53 and Rb tumor suppressor genes frequently inactivated in human prostate cancer. PB-Tag expression is hormonally regulated by androgens, and the onset of expression coincides developmentally with the onset of sexual maturity.

Consistent with observations in human prostate cancer, TRAMP mice will initially respond to androgen ablation demonstrating that prostate cancer in the model is initially androgen dependent. This is a unique feature of the TRAMP model, in contrast to other transgenic models that are androgen-independent. Following castration at 12 weeks of age approximately one-third of TRAMP mice show a durable response and remain tumor free. However, within 12 weeks post-castration, primary tumors are observed in two-thirds of mice. Interestingly, the androgen independent primary tumors in castrated mice are more poorly differentiated than in non-castrated controls. These mice also have an increased incidence of metastasis compared to intact TRAMP mice. This data is consistent with the hypothesis that molecular events leading to androgen independence can occur early in the natural history of the disease yet remain silent until androgen ablation provides selective pressure resulting in aggressive, metastatic prostate cancer.

All together, the TRAMP mice provide an autochthonous spontaneous model system to study the molecular basis of transformation of normal prostatic cells and the factors influencing the progression to metastatic and androgen-independent prostate cancer. Studies are currently underway to characterize the progression and development of prostate tumors at the molecular level.

In related studies, we are investigating whether a specifically altered form of the p53 tumor suppressor gene can be used to effectively treat prostate cancer. The strategy of this approach is to enhance apoptosis through expression of an altered p53 leading to tumor self-destruction. This represents a strategic alternative to anti-proliferative drugs that have demonstrated limited practical value in the treatment of advanced prostate cancer.

Finally, new transgenic studies have demonstrated that deregulation of the fibroblast growth factor signaling axis disrupts normal epithelial-mesenchymal signaling. Disrupting the flow of FGF signals from the mesenchyme to the epithlium leads to impaired prostate growth and development. Similar studies are underway to investigate the consequence of deregulated expression of the insulin like growth factor (IGF) axis on prostate growth, development and neoplasia.

The Mission Statement for The Norman Greenberg Lab is as follows:

1. To develop suitable autochthonous transgenic animal prostate cancer models to identify and characterize the molecular mechanisms involved in the genesis, progression, metastasis, and hormone insensitivity of prostate cancer, and

2. To develop and test novel strategies for prostate cancer prevention, diagnosis and therapy.