Mechanisms of Prostate Tumor Initiation: Interplay of Antioxidants and Genetic Alterations

Abstract

The high prevalence of prostate cancer makes it an attractive target for a widespread prevention measure. Oxidative stress has been implicated in prostate cancer, but the roles it plays throughout the stages of tumorigenesis are not completely understood. The recent Selenium and Vitamin E Cancer Prevention Trial (SELECT) showed that the antioxidants were unable to prevent prostate tumorigenesis and that vitamin E increased the risk of prostate cancer development in disease-free men. In order to investigate the role of oxidative stress in prostate tumor initiation, I supplemented a mouse model of early prostate tumorigenesis, Nkx3.1-/- mice, with the antioxidant N-acetylcysteine. Antioxidant supplementation promoted proliferation of the prostate epithelia and expression of a pro-proliferative gene expression signature, suggesting that oxidative stress may inhibit transformation in early prostate tumorigenesis in the setting of Nkx3.1-loss.

Therefore, as efficacy of prostate tumor chemoprevention may be determined by the presence of patient-specific risk factors, such as NKX3.1-deficiency, I analyzed the ability of NKX3.1 polymorphisms to modify risk associated with antioxidant supplementation in SELECT. I found that presence of an NKX3.1 functional variant increases the risk of prostate cancer upon antioxidant exposure. In addition, I identified an additional polymorphism in BNIP3L which modifies increased prostate cancer risk in the vitamin E arm of SELECT.

Interestingly, antioxidant function may promote or inhibit prostate tumor progression depending on the cell context. The antioxidant gene peroxiredoxin 6 (PRDX6) is a direct target gene of NKX3.1 and the oncogene MYC. I found that Prdx6 expression is depleted in several models of MYC-driven mouse prostate cancer, as would be consistent with a protein that inhibits prostate tumorigenesis. However, by overexpressing Prdx6 in the aggressive mouse prostate cancer cell line Myc-CaP, I showed that Prdx6 promotes in vitro and in vivo proliferation and anchorage-independent growth. Thus, the antioxidant protein Prdx6 may play a dual role in prostate tumorigenesis, serving an anti-tumorigenic role in early stages, and a pro-tumorigenic role in advanced cancer. My dissertation makes significant contributions to the understanding of oxidative stress in the development of prostate cancer.