Integration of Androgen and Growth Factor Signaling in Prostate Cancer

前列腺癌最初表现为一种雄激素依赖型疾病，因此可以通过减少雄激素来治疗。 治疗，如阉割。然而，有益的影响是短暂的，癌症总是进展到 对荷尔蒙消融不起作用。这些晚期前列腺癌中的大多数继续表达，显然 需要雄激素受体，但现在能够在非常低的去势的雄激素水平下生长。什么是 雄激素受体对低浓度雄激素的反应机制？ 在这些复发的癌症中，很大一部分表现为自分泌和旁分泌生长因子环的上调。 利用RAS信号，我们假设这种RAS介导的生长因子信号是 前列腺癌进展的贡献者。我们已经证明RAS信号与前列腺癌相关 在患者样本中，激活的RAS的表达足以推动进展，并且该表达 显性负性RAS使已进展为明显雄激素的细胞系恢复对雄激素的依赖 “独立。”重要的是，前列腺癌和受RAS刺激的前列腺癌细胞继续需要 功能正常的雄激素受体，但对极低水平的激素有反应。这项研究的目的是 建议了解RAS信号敏感的生化和分子途径。 雄激素受体到低水平的雄激素。我们提出了以下三个目标： 目的1.确定RAS家族成员和效应器在雄激素水平降低过程中的作用 依赖。RAS是一种多效应蛋白，是复杂蛋白家族的一员。我们将确定哪一个 这个信号网络的组成部分负责推动前列腺癌减少对激素的依赖。 目的2.确定RAS信号与雄激素受体生命周期的交叉点。我们会 确定RAS信号允许雄激素受体对低浓度的 雄激素，侧重于转录复合体的组装。 目的3.确定调节AR对雄激素敏感性的MAP-Kinase底物。RAS？&>MAP Kinase 途径是RAS改变生长和雄激素依赖机制的重要组成部分。 基因表达。一旦我们确定了RAS和MAP激酶信号和MAP的交点(S AR生命周期，我们将使用一个经过设计的“袖珍突变体”MAP Kinase和ATP类似物来识别直接MAP 酶底物。 这项研究将有助于理解类固醇和生长因子信号的整合，如 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.