Vav3 Oncogene Potentiation of Androgen Receptor Signaling in Prostate Cancer.

描述（由申请人提供）：雄激素受体（AR）是一种配体激活的转录因子，属于核受体家族，在前列腺癌的发生和进展中起关键作用。虽然雄激素剥夺治疗仍然是晚期和非器官局限性前列腺癌临床管理的基石，但大多数接受这种治疗的患者最终会复发。复发性疾病被称为雄激素非依赖性或激素难治性。雄激素非依赖性肿瘤不仅维持转录活性AR，它们甚至在雄激素耗尽的条件下也依赖于AR生长和存活。我们和其他人已经证明，Vav 3，一个Rho GT3鸟嘌呤核苷酸交换因子（GEF），在体外和体内前列腺癌的发展过程中，在几个模型中，以及在男性接受雄激素剥夺治疗雄激素非依赖性上调。此外，Vav 3蛋白在约三分之一的人前列腺癌中过表达。我们已经证明，Vav 3是在雄激素存在或不存在的情况下前列腺癌细胞中AR转录活性的有效增强剂。在雄激素存在下，Vav 3增强AR转录活性（共激活）不需要Vav 3 GEF活性。此外，我们的初步数据显示，Vav 3而不是Vav 3 W 493 L（普列克底物蛋白同源（PH）结构域突变体）被募集到染色质中的AR靶基因雄激素响应区。这种招募以雄激素依赖的方式发生，并揭示了Vav 3的新的核作用。相比之下，致癌（组成型活性）Vav 3（或由生长因子激活的Vav 3）通过需要Vav 3 GEF功能和Rho GT3，Rac 1的串扰促进配体非依赖性AR激活。因此，Vav 3是AR活性的通用调节剂。Vav 3对AR的依赖性和非依赖性激活都可能有助于前列腺癌的进展，并且这两种途径都是治疗上可利用的。该项目的潜在影响是高的，由于抑制Rac 1的药物的可用性。本研究将探讨Vav 3增强AR转录活性和前列腺癌进展为雄激素非依赖性的机制。我们将确定Vav 3/Rac 1信号传导是否是必要的，足以导致雄激素非依赖性肿瘤形成的肿瘤异种移植研究和基因工程小鼠模型的前列腺癌。我们将定义Vav 3增强AR活性在此过程中的作用。在小鼠模型中鉴定Vav 3增强AR活性的分子机制和检查Vav 3对前列腺癌进展的贡献对于开发Vav 3途径作为治疗靶点至关重要。公共卫生相关性：相关性：人类前列腺癌中Vav 3蛋白水平升高。Vav 3增强雄激素受体的活性，增加前列腺癌细胞的生长并导致小鼠前列腺癌。本研究旨在了解Vav 3的这些致癌作用，以利用目前可用的靶向Vav 3通路的药物用于前列腺癌治疗。

DESCRIPTION (provided by applicant): The androgen receptor (AR), a ligand-activated transcription factor and member of the nuclear receptor family, plays a key role in the development and progression of prostate cancer. While androgen deprivation therapy remains the cornerstone of clinical management for advanced and non-organ confined prostate cancer, the majority of patients undergoing this treatment eventually relapse. The recurrent disease is termed androgen independent or hormone refractory. Androgen independent tumors not only maintain transcriptionally active AR, they are dependent on AR for growth and survival even under androgen-depleted conditions. We and others have demonstrated that Vav3, a Rho GTPase guanine nucleotide exchange factor (GEF), is upregulated during in vitro and in vivo progression of prostate cancer to androgen-independence in several models as well as in men undergoing androgen deprivation therapy. Further, Vav3 protein is overexpressed in approximately one-third of human prostate cancer. We have demonstrated that Vav3, is a potent enhancer of AR transcriptional activity in prostate cancer cells in the presence or absence of androgen. Vav3 potentiation of AR transcriptional activity in the presence of androgen (coactivation) does not require Vav3 GEF activity. Further, our preliminary data show that Vav3 but not Vav3 W493L (a pleckstrin homology (PH) domain mutant) is recruited to an AR target gene androgen responsive region in chromatin. This recruitment occurs in an androgen-dependent manner and reveals a novel nuclear role for Vav3. In contrast, oncogenic (constitutively active) Vav3 (or Vav3 activated by growth factors) promotes ligand-independent AR activation via cross-talk that requires Vav3 GEF function and the Rho GTPase, Rac1. Thus, Vav3 is a versatile modulator of AR activity. Both the hormone-dependent and -independent activation of AR by Vav3 may contribute to prostate cancer progression and both pathways are exploitable therapeutically. The potential impact of this project is high due to the availability of drugs that inhibit Rac1. This study will investigate the mechanisms by which Vav3 enhances AR transcriptional activity and prostate cancer progression to androgen independence. We will determine whether Vav3/Rac1 signaling is necessary and sufficient to cause androgen independent tumor formation in tumor xenograft studies and in genetically engineered mouse models of prostate cancer. We will define the role of Vav3 enhancement of AR activity in this process. Identification of the molecular mechanisms of Vav3 potentiation of AR activity and examination of the contribution of Vav3 to prostate cancer progression in mouse models is essential for the development of Vav3 pathways as therapeutic targets. PUBLIC HEALTH RELEVANCE: RELEVANCE: Levels of the Vav3 protein rise in human prostate cancer. Vav3 enhances the activity of the androgen receptor, increases growth of prostate cancer cells and causes prostate cancer in mice. This study seeks to understand these oncogenic effects of Vav3 in order to exploit currently available drugs that target Vav3 pathways for prostate cancer therapy.