Prostate adenocarcinoma has the highest incidence of any malignancy and is the second leading cause of cancer-related deaths in men in the United States. The development and progression of prostate cancer are dependent on signals from androgenic hormones for the positive regulation of tumor growth and negative influence on cell death. As a result, the inhibition of androgens has been the primary therapy for metastatic prostate cancer, and much effort has been devoted to elucidating the role of the androgen receptor in prostate cancer. Androgen deprivation reduces clinical symptoms in about 80% of these patients, but unfortunately most tumors relapse within 2 years to an androgen-independent stage. The mechanisms behind the transition to androgen-independent growth are unknown, but locally synthesized factors that regulate cell proliferation and cell death are probably involved. One such factor, transforming growth factor-beta (TGF-beta), plays an important part in mediating the cell death associated with androgen removal. TGF-beta communicates to cells via specific cell surface receptors. It is interesting that the loss of expression of these TGF-beta receptors by the prostate cancer cells indicate a poorer clinical prognosis.

Our preliminary studies involving the characterization of mouse models indicate the stromal supporting cells of the prostate as the primary mediator of TGF-beta actions on prostatic development, androgen responsiveness, and transformation, such that the deletion of the TGF-beta receptor in the supporting cells resulted in the spontaneous development of pre-neoplastic lesions and diminished responsiveness to androgen-removal therapy. Thus, we hypothesized that TGF-beta signaling in these prostatic supporting cells contributes to normal prostatic epithelial differentiation; when this signal is diminished in cancer, the functionality of the prostate is altered. We aim to understand how the loss of TGF-beta receptor expression in the prostate stroma affects the growth, cell death, and metastatic potential of prostate cancer. We also aim to address the consequences of the loss of TGF-beta receptor expression in the prostate cancer cells themselves.

The complexity of the signals involved in the progression of prostate cancer obviates our use of genetically engineered mice, prostate cancer tissue grafts, and prostate cancer cells in culture to appropriately model and interrogate the mechanism.