Rad9-Based Mouse Model of Prostate Carcinogenesis

点击翻译按钮获取中文摘要

DESCRIPTION (provided by applicant): When cells are exposed to physical or chemical agents that damage DNA, deleterious effects can ensue, including mutation, cancer or death. However, mechanisms are available to repair the damage, stabilize the genome and neutralize harmful effects. We isolated and characterized an evolutionarily conserved gene called Rad9, from yeast, mouse and human, which is critical for maintaining genomic stability and promoting cellular resistance to DNA damage. Based on these as well as other findings, we examined the role of Rad9 in carcinogenesis, and found a significant link in particular to prostate cancer. Our results include the observation that Rad9 is dramatically overexpressed in four commonly used prostate cancer cell lines, CWR22, DU145, LNCaP and PC-3, relative to normal human prostate PrEC cells and the immortalized but nontumorigenic cell line PWRE-1. We also found that the degree to which siRNA reduces Rad9 protein levels correlates with the extent of decrease in tumorigenicity of these cells after injection into nude mice. Moreover, nontumorigenic immortalized PWRE-1 cells can form aberrant growths in nude mice if the cells are engineered to overproduce Rad9. In addition, we detected high Rad9 protein levels in 153 of 339 (45.1%) human prostate adenocarcinomas, but just low abundance in 2 of 52 normal prostate tissue controls. Relatively higher levels of Rad9 protein were in general associated with more advanced disease. Our results thus indicate that Rad9 plays a functional role in prostate carcinogenesis. This project focuses on the hypothesis that aberrantly high abundance of Rad9 protein leads to prostate cancer. The major experimental goal is to create and characterize a novel mouse model of prostate carcinogenesis, based on aberrant high expression of Rad9 specifically in that organ. To this end, we have preliminary data indicating that such a line of mouse has been constructed. Specific aims of the study focus on 1) examining prostate tissue of parental, as well as transgenic mice with high levels of Rad9 in prostate with respect to spontaneous as well as radiation-induced formation of prostate tissue abnormalities and tumorigenesis as a function of age; 2) determine the relationship between high levels of Rad9 and spontaneous as well as ionizing radiation-induced metastatic prostate cancer; and 3) defining the relationship between the ability of high levels of Rad9 to mediate prostate disease and expression of downstream target genes of the transactivity function of Rad9 as well as expression of other genes well-established to be intimately involved in prostate cancer, to begin to understand the mechanistic basis for Rad9 mediated prostate carcinogenesis. In the end, this project will provide a unique model to define molecular mechanisms of prostate carcinogenesis, and serve as an in vivo system for elucidating risk o environmental carcinogenesis. PUBLIC HEALTH RELEVANCE: This proposal focuses on the role of Rad9 in mediating prostate carcinogenesis. The goal is to engineer and characterize a unique mouse model demonstrating genetic predisposition to this kind of cancer, based on high levels of Rad9 protein in prostate. The spontaneous as well as radiation-induced development of prostate disease will be assessed. As such, this project is important since the results could impact on human health, both in terms of treatment for prostate cancer and understanding the interplay of genetics and the environment with respect to carcinogenesis.