Integration of Androgen and Growth Factor Signaling in Prostate Cancer

前列腺癌中雄激素和生长因子信号的整合

• 批准号: 7728881
• 负责人: MICHAEL J. WEBER
• 金额: $ 22.08万
• 依托单位: UNIVERSITY OF VIRGINIA
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-08-01 至 2010-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7728881
• 关键词: Ablation; Androgen Receptor; Androgens; Animals; Automobile Driving; Binding; Biochemical; Biochemical Pathway; Biological; Biological Assay; Bypass; Castration; Cell Line; Cells; Characteristics; Clinical; Collaborations; Complex; Cultured Cells; Cyclic AMP-Dependent Protein Kinases; DNA; Databases; Dependence; Disease; Dominant-Negative Mutation; Engineering; Environment; Family; Family member; GTP-Binding Proteins; Gene Expression; Genetic; Genetic Epistasis; Goals; Gold; Growth; Growth Factor; Growth Factor Receptors; HRAS gene; Hormones; Human; Intention; Investments; Knowledge; Link; MAP2K1 gene; Malignant Neoplasms; Malignant neoplasm of prostate; Mass Spectrum Analysis; Mediating; Mentors; Mitogen-Activated Protein Kinases; Molecular; Mutate; Nuclear; Oncogenes; Other Resources; Paraffin Embedding; Pathway interactions; Patients; Phenotype; Phospho-Specific Antibodies; Phosphorylation Site; Phosphotransferases; Protein Family; Protein Isoforms; Protein Overexpression; Proteins; Proteomics; Publications; Range; Reagent; Receptor Signaling; Recurrent Malignant Neoplasm; Refractory; Reporting; Research; Research Infrastructure; Research Proposals; Role; Sampling; Scaffolding Protein; Signal Pathway; Signal Transduction; Signaling Molecule; Small Interfering RNA; Specimen; Standards of Weights and Measures; Steroids; Techniques; Technology; Transcriptional Regulation; Up-Regulation; Work; Xenograft procedure; analog; autocrine; base; bone; cancer cell; implantation; knock-down; member; mutant; nucleocytoplasmic transport; paracrine; programs; ras Proteins; receptor; receptor binding; receptor function; receptor sensitivity; research study; scaffold; therapeutic target; tumor progression

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.

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