Targeting BRM as novel model of prostate hyperplasia

描述（由申请人提供）：特异性SWI/SNF亚基的缺失与受损的分化、异常增殖和肿瘤发生相关。SWI/SNF染色质重塑复合物通过选择的序列特异性转录因子被募集到DNA，并利用ATP水解的能力来改变染色质结构和基因转录。每个SWI/SNF复合物由中央ATP酶（BRM或BRG 1）和大约8-10个相关蛋白质（对于BRG 1相关因子，被认为是BAF）的组合组装体组成，其为SWI/SNF作用提供特异性。动物模型显示，BRM通常在分化的细胞中表达，而BRG 1优先在未分化的细胞类型中表达。因此，前列腺腔上皮细胞表达BRM，但不表达BRG 1。虽然BRM基因座的改变尚未研究，但已知包含BRM（9 p22 -24）的区域在人类前列腺癌中丢失。此外，9号染色体的单体性已观察到高频率。我们以前已经证明，BRM相关的SWI/SNF复合物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）刺激靶基因转录的能力所必需的。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来阻止细胞周期进程。鉴于AR和RB在控制雄激素依赖性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。使用Brm -/-小鼠，我们证明了BRM功能的消融导致早期显著增生，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表达在前列腺癌中减少。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，该探索性R21提案旨在：1）表征在Brm -/-小鼠中观察到的增生性病变，2）使用组织重组直接确定BRM损失对前列腺上皮细胞的影响。所描述的研究将建立该模型用于分析前列腺癌的效用，并揭示前列腺中BRM损失的生物学后果。

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.