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选择序列特异性转录因子被招募到DNA中，并利用ATP水解的力量改变染色质结构和基因转录。每个SWI/SNF复合物由一个中心atp酶（BRG1或BRM）和大约8-10个相关蛋白（BRG1相关因子称为baf）的组合组装而成，这些蛋白赋予SWI/SNF作用的特异性。动物模型显示BRM通常在已分化的细胞中表达，而BRG1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而不表达BRG1。虽然BRM位点的改变尚未被研究，但已知含有BRM （9p22-24）的区域在人类前列腺癌中丢失。此外，9号染色体的单体现象也有较高的发生率。我们之前已经证明，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，我们证明了雄激素受体（AR）刺激靶基因转录的能力需要BRM。其次，我们和其他人证明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Brm功能的消融导致早期显著增生，并伴有潜在的侵袭和对雄激素的超敏反应。我们还提供数据证明前列腺癌中BRM表达减少。这些数据支持了BRM在前列腺中具有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，本探索性R21提案旨在：1)表征Brm -/-小鼠中观察到的增生病变；2)通过组织重组直接建立Brm缺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前列腺癌分析的效用，并揭示前列腺中BRM丢失的生物学后果。

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.