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Title page for ETD etd-07242013-155857


Type of Document Dissertation
Author Martinez, Erin Elizabeth
URN etd-07242013-155857
Title Mechanisms of Prostate Tumor Initiation: Interplay of Antioxidants and Genetic Alterations
Degree PhD
Department Pathology
Advisory Committee
Advisor Name Title
Larry Swift, Ph.D. Committee Chair
Bill Valentine, D.V.M., Ph.D. Committee Member
Christine Eischen, Ph.D. Committee Member
Sarki Abulkadir, M.D., Ph.D. Committee Member
Simon Hayward, Ph.D. Committee Member
Keywords
  • prostate cancer
  • NKX3.1
  • SELECT
  • BNIP3L
  • chemoprevention
Date of Defense 2013-07-09
Availability unrestricted
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.

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