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，是核受体家族的成员，在前列腺癌的发生和发展中起着关键作用。虽然雄激素剥夺疗法仍然是晚期和非器官局限性前列腺癌临床治疗的基石，但大多数接受这种治疗的患者最终会复发。复发性疾病称为雄激素非依赖型或激素难治性疾病。雄激素非依赖性肿瘤不仅维持转录活性AR，即使在雄激素缺乏的条件下，它们也依赖AR来生长和生存。我们和其他人已经证明，在几种模型以及接受雄激素剥夺治疗的男性中，Rho GTPase鸟嘌呤核苷酸交换因子（GEF） Vav3在体外和体内前列腺癌向雄激素依赖性发展的过程中上调。此外，Vav3蛋白在大约三分之一的人类前列腺癌中过表达。我们已经证明，无论雄激素存在与否，Vav3都是前列腺癌细胞中AR转录活性的有效增强子。在雄激素存在的情况下，Vav3增强AR转录活性（共激活）并不需要Vav3 GEF活性。此外，我们的初步数据表明，Vav3而不是Vav3 W493L（一种pleckstrin同源（PH）结构域突变体）被招募到染色质上的AR靶基因雄激素响应区域。这种招募以雄激素依赖的方式发生，揭示了Vav3的一种新的核作用。相反，致癌（组成活性）Vav3（或由生长因子激活的Vav3）通过串扰促进配体非依赖性AR激活，这需要Vav3 GEF功能和Rho GTPase， Rac1。因此，Vav3是AR活性的多功能调制器。Vav3对AR的激素依赖性和非依赖性激活都可能促进前列腺癌的进展，这两种途径都可用于治疗。由于抑制Rac1的药物的可用性，该项目的潜在影响很高。本研究将探讨Vav3增强AR转录活性和前列腺癌向雄激素独立发展的机制。我们将在肿瘤异种移植研究和前列腺癌基因工程小鼠模型中确定Vav3/Rac1信号是否必要和充分导致雄激素非依赖性肿瘤形成。我们将定义Vav3在这一过程中增强AR活性的作用。确定Vav3增强AR活性的分子机制，并在小鼠模型中研究Vav3对前列腺癌进展的贡献，对于开发Vav3通路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Vav3蛋白水平升高。Vav3增强雄激素受体的活性，增加前列腺癌细胞的生长，并在小鼠中引起前列腺癌。本研究旨在了解Vav3的这些致癌作用，以便开发目前可用的靶向Vav3途径的前列腺癌治疗药物。

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.