Vav3 Oncogene Potentiation of Androgen Receptor Signaling in Prostate Cancer.

雄激素受体(AR)，一种配体激活的转录因子，是核受体的成员 家族在前列腺癌的发生发展中起着关键作用。当雄激素被剥夺时 治疗仍然是晚期非器官受限前列腺癌临床治疗的基石， 接受这种治疗的大多数患者最终会复发。这种复发性疾病被称为 雄激素非依赖性或激素耐受性。雄激素非依赖性肿瘤不仅维持 转录活跃的AR，即使在雄激素耗竭的情况下，它们的生长和生存也依赖AR 条件。我们和其他人已经证明了Vav3，一种Rho GTP酶鸟嘌呤核苷酸交换因子 在体外和体内前列腺癌向雄激素非依赖性发展过程中， 几个模型以及正在接受雄激素剥夺治疗的男性。此外，Vav3蛋白是 在大约三分之一的人类前列腺癌中过度表达。我们已经演示了Vav3，是一种 在存在或不存在雄激素的情况下，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，AR转录活性的Vav3增强(共激活)不需要 Vav3全球环境基金活性。此外，我们的初步数据表明，Vav3而不是Vav3 W493L(Pleckstrin同源 (PH)域突变体)被招募到染色质中的AR靶基因雄激素反应区。这 募集以雄激素依赖的方式发生，并揭示了Vav3的一个新的核角色。相比之下， 致癌(成分活性)Vav3(或由生长因子激活的Vav3)促进配体非依赖性AR 通过串扰激活，需要Vav3全球环境基金功能和Rho GTPase，rac1。因此，Vav3是一款多功能的 AR活性的调节剂。Vav3对AR的激素依赖性和非依赖性激活均可 有助于前列腺癌的进展，这两条途径都可以在治疗上利用。潜力 这个项目的影响很大，因为有抑制rac1的药物可用。这项研究将调查 Vav3增强AR转录活性和前列腺癌向雄激素进展的机制 独立。我们将确定Vav3/rac1信号是否是产生雄激素的必要条件和充分条件 在肿瘤异种移植研究和基因工程小鼠模型中的独立肿瘤形成 前列腺癌。我们将确定Vav3增强AR活性在这一过程中的作用。身份识别 Vav3增强AR活性的分子机制及Vav3对AR活性的贡献 小鼠模型中前列腺癌的进展是Vav3通路作为治疗手段发展的关键 目标。

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.