Investigating the role of the Rb pathway in prostate tumor suppression

Abstract

Prostate cancer arises from multiple genetic changes in specific genes and a major challenge in understanding this disease is defining the precise role these genetic alterations play in cancer development. Tumor biopsies have shown that Rb mutations occur in approximately 50% of human prostate tumors and the p53 tumor suppressor gene is mutated frequently in more advanced forms of this disease. Although animal models have begun to uncover mechanisms for pRb_f and p53 inactivation together, the individual roles of these factors in the etiology of prostate cancer remains unclear and has not yet been explored in vivo. We have directly tested the impact of pRb_f inactivation alone in the prostate epithelium using a transgenic mouse model. The full T antigen oncoprotein (which inactivates both pRb_f and p53) has been shown to induce prostate tumors in transgenic mice. Here, T₁₂₁, a modified T antigen that inactivates only pRb_f, has been expressed by a prostate-epithelium-specific promoter (ARR2PB) to test the role of pRb_f inactivation alone in prostate tumorigenesis. We have determined that inactivation of just the pRb family in mice is sufficient to cause prostatic intraepithelial neoplasias (PIN) in these APT121 mice that resemble those seen in humans. Characteristic traits of High Grade PIN have been observed as early as nine weeks of age. Older animals (4.5 months) show stromal thickening, cribiform epithelium and early signs of adenocarcinoma. The difficulty in developing effective treatment for these most aggressive stages of prostate cancer is that these neoplasias develop from a wide range of changes in multiple genes. Defining the precise role that these genetic changes play in these tumors would be a large step toward understating how to better treat patients with this disease. Further analysis using knock out strains has been carried out to address the role of p53 and PTEN inactivation, which are hypothesized to contribute to prostate tumor progression. Our preliminary work suggests that inactivation of PTEN causes a decline in cell death and acceleration of tumor progression. Aggressive prostate tumor growth was noted in APT₁₂₁ p53^+/− from 7-9 months of age. Analysis of these large, rapid-growing tumors indicated that they are heterogeneous and multifocal in nature, and largely consist of phylloides tumors, which are comprised of a large stromal component. The presence of apoptotic bodies in APT121/p53 heterozygous and APT121/p53 nullizygous mice indicate that while these lesions are progressing, it is not due to loss of p53 dependent apoptosis. We believe that these studies will greatly facilitate the study of prostate tumor progression mechanisms and produce a valuable preclinical model of prostate cancer.