Targeting BRM as novel model of prostate hyperplasia

描述(由申请人提供)：特定的SWI/SNF亚基缺失与分化受损、异常增殖和肿瘤发生有关。SWI/SNF染色质重塑复合体通过特定的序列转录因子被招募到DNA上，并利用ATP水解力改变染色质结构和基因转录。每个SWI/SNF复合体由一个中央ATPase(BRG1的BRM)和大约8-10个相关蛋白(被认为是BRG1相关因子的BAFs)组成的组合组装，这为SWI/SNF的作用提供了特异性。动物模型显示，BRM通常在分化的细胞中表达，而BRG1在未分化的细胞类型中优先表达。因此，前列腺腔上皮细胞表达BRM，但不表达BRG1。虽然BRM基因座的改变尚未被研究，但已知含有BRM(9p22-24)的区域在人类前列腺癌中丢失。此外，9号染色体单体的出现频率也很高。我们之前已经证明，BRM相关的SWI/SNF复合体调节与前列腺癌进展和发展相关的关键转录因子。首先，我们证明了BRM是雄激素受体(AR)刺激靶基因转录所必需的。其次，我们和其他人证明了视网膜母细胞瘤肿瘤抑制蛋白(RB)需要SWI/SNF来阻止细胞周期进展。鉴于AR和Rb在调节雄激素依赖的增殖和分化中的重要作用，我们探讨了体内BRM缺失对前列腺细胞增殖的影响。利用BRM-/-小鼠，我们证明了去除BRM功能会导致早期显著的增生，具有潜在的侵袭性和对雄激素的超敏反应。我们还提供了数据来证明BRM在前列腺癌中的表达减少。这些数据支持BRM在前列腺中发挥重要的生长抑制功能的假设。鉴于前列腺增生和癌症模型的缺乏，这一探索性的R21建议旨在：1)表征在BRM-/-小鼠中观察到的增生性病变，以及2)通过组织重组直接建立BRM丢失对前列腺上皮细胞的影响。所描述的研究将建立该模型在前列腺癌分析中的实用性，并揭示前列腺癌BRM缺失的生物学后果。

DESCRIPTION (provided by applicant): 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.