Effects of Phthalates on Androgen Receptor Regulation Associated with Castration-Resistant Prostate Cancer Development
[Technical Report, Annual Report]
University of Wisconsin System
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Androgen deprivation therapy is initially effective for most prostate cancer patients, but it recurs after several years and becomes resistant, defined as castration-resistant prostate cancer CRPC. The molecular mechanisms of the transition to CRPC are poorly understood. The androgen receptor AR is known to play a key role in the prostate cancer progression. Numerous mechanisms were introduced to show how CRPC continues to grow through AR signaling. Current CRPC therapies are mostly aimed to either inhibit AR expression or block androgen biosynthesis based on those findings. However, there is considerable population of CRPC patients that are typically ignored, showing a loss of AR in the tumor. For this group of patients, current treatments are ineffective. However, little research is conducted to investigate the pathways that are associated with the AR negative CRPC development. Therefore, the overall goal is to elucidate molecular mechanisms involved in the CRPC development specifically in the AR negative cell population. Nowadays, high attention is given to the effects of environmental toxicants on biological systems because we are all exposed to these environmental factors for decades and many studies have shown association of environmental toxicant exposure with adverse health outcomes. Phthalates are widely used in plastics and many everyday products. However, very little is known of their impacts on PRCA progression. The proposed project will investigate the effects of phthalates on AR regulation at molecular levels and determine its role in the CRPC development. This project will use PRCA models both in vitro and in vivo. PRCA xenografts will be implanted into mice and assessed for PRCA-aggressiveness. Additionally, AR levels and their epigenetic alterations will be measured.
- Medicine and Medical Research