Androgen Receptor Coregulators in Prostate Cancer

Project Details

Description

DESCRIPTION (Provided by the applicant)

Regulation of gene expression by the androgen receptor (AR) involves the
association and action of transcriptional coregulatory proteins. Although a
plethora of AR-interacting proteins have been identified, the physiological and
pathological roles fulfilled by these factors in AR-mediated signaling pathways
remain poorly understood. The goal of this application is to investigate and
characterize the involvement of specific AR-coregulatory factors during normal
prostate growth and the progression of prostate tumorigenesis. Given that
prostate cancer cells are initially androgen-dependent and eventually progress
into androgen-independent cells, we hypothesize that neoplastic changes in AR
signaling pathways and/or the AR protein itself can abnormally affect the
specific types of coregulatory protein complexes that bind to the receptor. To
address these issues, we will generate stable FLAG epitope-tagged AR (f:AR)
expressing cell lines from immortalized primary prostate cells (normal and
malignant) and from metastatic prostate tumor cells. The lines will serve as
biological tools with which we will immunoaffinity purify f:AR from hormone
treated (and untreated) cells and subsequently examine and characterize the
AR-associated proteins using a number of biochemical techniques. Our specific
goals are to: (1) Determine whether distinct types of transcriptional
coregulatory proteins are differentially associated with f:AR in normal versus
malignant prostate cells. Stable f:AR-expressing prostate lines will be
cultured in the presence (or absence) of distinct androgens and anti-androgens;
f:AR-cofactor complexes will be purified and characterized by silver stain,
Western blotting and mass spectrometry. (2) Determine whether
androgen-independent signaling pathways induce f:AR-cofactor complex assembly
in normal and malignant prostate cells. These studies will examine whether
activation of specific receptor tyrosine kinases (previously implicated in
prostate cancer and androgen-independent growth) can trigger specific f:
AR-cofactor complex formation in the absence of AR ligands. (3) Determine
whether pathologically associated mutations/polymorphisms in the AR gene affect
f:AR-cofactor assembly. The f:AR cDNA will be subjected to site-directed
mutagenesis and subsequently stably introduced into prostate cells. The mutated
f:AR will be purified from ligand-treated cells and the associated cofactors
identified and characterized. In summary, the studies outlined here should
increase our fundamental understanding of the role of coregulatory factors in
AR-mediated signaling pathways and potentially identify and define new targets
for therapeutic agents in the treatment of prostate cancer.
StatusFinished
Effective start/end date9/30/018/31/06

Funding

  • National Institute of Diabetes and Digestive and Kidney Diseases: $4,497.00
  • National Institute of Diabetes and Digestive and Kidney Diseases: $272,125.00
  • National Institute of Diabetes and Digestive and Kidney Diseases: $272,125.00
  • National Institute of Diabetes and Digestive and Kidney Diseases: $255,378.00
  • National Institute of Diabetes and Digestive and Kidney Diseases: $272,125.00

ASJC

  • Medicine(all)
  • Oncology
  • Cancer Research

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