Integration of Androgen and Growth Factor Signaling in Prostate Cancer

前列腺癌首先表现为雄激素依赖性疾病，因此可以通过减少雄激素来治疗 治疗，如阉割。然而，有益的效果是短暂的，癌症总是进展到 变得对激素消融不敏感。大多数晚期前列腺癌，继续表达， 需要雄激素受体，但现在能够在非常低的去势水平下生长。有哪些 雄激素受体对低浓度雄激素产生反应的机制？ 这些复发性癌症的显著部分显示自分泌和旁分泌生长因子环的上调 我们假设这种Ras介导的生长因子信号传导是一种主要的 前列腺癌的发展。我们已经证明Ras信号与前列腺癌相关， 在患者样品中，激活的Ras的表达足以驱动进展，并且该表达 显性负性Ras恢复了已发展为明显雄激素的细胞系的雄激素依赖性 “独立。“重要的是，前列腺癌和用Ras刺激的前列腺癌细胞仍然需要一个持续的时间。 功能性雄激素受体，但对非常低水平的激素有反应。本研究的目的 这项研究的目的是了解Ras信号转导使细胞内的蛋白质敏感的生化和分子途径。 雄激素受体对低水平的雄激素。我们提出以下三个目标： 目标1。确定Ras家族成员和效应子在雄激素减少进展中的作用 依赖Ras是一种多效应蛋白，是复杂蛋白家族的成员。我们将决定 该信号网络的组分负责驱动前列腺癌降低激素依赖性。 目标二。确定Ras信号传导和雄激素受体生命周期之间的交叉点。我们将 确定Ras信号传导的靶点，这些靶点允许雄激素受体对低浓度的 雄激素，专注于转录复合物的组装。 目标3：确定调节AR对雄激素敏感性的MAP激酶底物。Ras <$> MAP激酶 途径是Ras改变生长的雄激素依赖性的机制的重要组成部分， 基因表达。一旦我们确定了Ras MAP激酶信号传导和蛋白激酶信号传导之间的交叉点， AR的生命周期，我们将使用一种工程化的“口袋突变体”MAP激酶和ATP类似物来鉴定直接MAP 激酶底物。 这项研究将有助于了解类固醇和生长因子信号传导的整合， 以及确定晚期前列腺癌的最佳治疗靶点。

Prostate cancer first presents as an androgen dependent disease, and can thus be treated with androgen reduction therapies, such as castration. The beneficial effects, however, are transitory, and the cancer invariably progresses to become refractory to hormone ablation. Most of these advanced prostate cancers, continue to express and apparently require the Androgen Receptor, but are now capable of growing at very low, castrate, levels of androgen. What are the mechanisms by which the Androgen Receptor becomes responsive to low androgen concentrations? A significant portion of these recurrent cancers display upregulation of autocrine and paracrine growth factor loops that utilize Ras signaling, and we hypothesize that this Ras-mediated growth factor signaling is a major contributor to prostate cancer progression. We have shown that Ras signaling correlates with prostate cancer progression in patient samples, that expression of activated Ras is sufficient to drive progression, and that expression of dominant negative Ras restores androgen dependence to a cell line that had progressed to apparent androgen "independence." Importantly, both prostate cancers and prostate cancer cells stimulated with Ras continue to require a functional Androgen Receptor but become responsive to very low levels of hormone. The goal of this research proposal is to understand the biochemical and molecular pathways by which Ras signaling sensitizes the Androgen Receptor to low levels of androgen. We propose the following three aims: Aim 1. Determine the roles of Ras family members and effectors in progression to decreased androgen dependence. Ras is a multi-effector protein and a member of a complex protein family. We will determine which components of this signaling network are responsible for driving prostate cancer to reduced hormone dependence. Aim 2. Identify the intersection point between Ras signaling and the Androgen Receptor lifecycle. We will determine the targets of Ras signaling that allow the Androgen Receptor to respond to low concentrations of androgen, focusing on assembly of transcriptional complexes. Aim 3. Identify the MAP Kinase substrates that regulate AR sensitivity to androgen. The Ras ¿> MAP Kinase pathway is an essential component of the mechanisms by which Ras alters androgen dependence of growth and gene expression. Once we have identified the intersection point(s) between Ras ¿> MAP Kinase signaling and the AR lifecycle, we will use an engineered "pocket mutant" MAP Kinase and ATP analogs to identify direct MAP Kinase substrates. This research will be informative with respect to understanding the integration of steroid and growth factor signaling, as well as in identifying the optimal therapeutic targets for advanced prostate cancer.