Loss of specific SWI/SNF subunits is associated with compromised differentiation, aberrant proliferation and tumorigenesis. SWI/SNF chromatin remodeling complexes are recruited to DNA by selected sequence-specific transcription factors, and use the power of ATP hydrolysis to alter chromatin structure and gene transcription. Each SWI/SNF complex is composed of a combinatorial assembly of a central ATPase (either BRM of BRG1), and approximately 8-10 associated proteins (deemed BAFs, for BRG1 associated factors), which lend specificity to SWI/SNF action. Animal models have revealed that BRM is typically expressed in differentiated cells, whereas BRG1 is preferentially expressed in undifferentiated cell types. Accordingly, prostatic luminal epithelial cells express BRM but not BRG1. Although alterations of the BRM locus have not been studied, the region containing BRM (9p22-24) is known to be lost in human prostate cancer. Moreover, monosomy of chromosome 9 has been observed with high frequency. We have previously demonstrated that BRM-associated SWI/SNF complexes regulate critical transcription factors associated with prostate cancer progression and development. First, we demonstrated that BRM is required for the ability of the androgen receptor (AR) to stimulate target gene transcription. Second, we and others demonstrated that the retinoblastoma tumor suppressor protein (RB) requires SWI/SNF to halt cell cycle progression. Given the important roles of AR and RB in governing androgen dependent proliferation and differentiation, we probed the impact of BRM loss in vivo on cellular proliferation in the prostate. Using Brm -/- mice we demonstrate that ablation of BRM function results in early, significant hyperplasia with potential invasion and hypersensitivity to androgen. We also present data to demonstrate that BRM expression is reduced in prostate cancer. These data support the hypothesis that BRM serves an important growth suppressive function in the prostate. Given the paucity of models for prostatic hyperplasia and cancer, this exploratory R21 proposal is designed to: 1) characterize the hyperplastic lesions observed in Brm -/- mice and 2) directly establish the impact of BRM loss on prostatic epithelial cells using tissue recombination. The studies described will establish the utility of this model for analysis of prostate cancer, and reveal the biological consequence of BRM loss in the prostate. ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Exploratory/Developmental Grants (R21)
Project #
1R21CA121402-01A1
Application #
7141558
Study Section
Special Emphasis Panel (ZRG1-ONC-U (90))
Program Officer
Woodhouse, Elizabeth
Project Start
2006-09-01
Project End
2008-08-30
Budget Start
2006-09-01
Budget End
2007-08-31
Support Year
1
Fiscal Year
2006
Total Cost
$148,200
Indirect Cost
Name
University of Cincinnati
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
041064767
City
Cincinnati
State
OH
Country
United States
Zip Code
45221
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