The effects of PTEN on tyrosine kinase signaling in Breast Cancer

项目总结/摘要 这些研究的目的是了解肿瘤抑制因子磷酸酶和 乳腺癌中10号染色体上的张力蛋白同源物缺失（PTEN）及其功能对乳腺癌发生的影响 酪氨酸激酶信号传导。磷脂酰肌醇-3激酶（PI 3 K）通路的异常激活是导致细胞凋亡的原因之一。 人类癌症中最常见的分子改变，最常见的是表达缺失或功能缺失 PTEN突变。PTEN作为PI 3 K下游的脂质磷酸酶拮抗PI 3 K信号传导，但 PTEN蛋白磷酸酶活性具有肿瘤抑制作用，其作用尚未解决。PTEN缺陷 导致包括胰岛素样生长因子-I受体（IGF-IR）的受体酪氨酸激酶（RTK）的活化， 胰岛素受体（InsR）和ErbB 3/HER 3，暗示PTEN在上游和下游信号传导的调节中起作用。 在PI 3 K的下游。因此，我假设1）PTEN蛋白的肿瘤抑制作用 磷酸酶活性涉及包括RTK在内的癌蛋白的直接去磷酸化，和2）PTEN丢失 使癌细胞对RTK抑制敏感。支持假设#1的结果表明， 不仅增加PI 3 K通路信号传导，而且通过蛋白质介导的 路径仍有待确定。在这种情况下，PI 3 K抑制可能不足以阻断肿瘤细胞的生长。 PTEN缺陷型肿瘤。支持假设#2的结果将提供PTEN缺失作为患者的生物标志物。 可能受益于RTK定向治疗的亚群。为了验证这些假设，我提出以下建议 具体目的：1）确定PTEN的缺失是否调节IGF-I、胰岛素和HER 3受体信号传导; 2)确定PTEN缺失是否对IGF-IR、InsR和HER 3的治疗性抑制剂敏感; 3） 发现了PTEN的磷蛋白底物和PTEN蛋白磷酸酶活性对 酪氨酸激酶信号传导。PTEN蛋白质底物的总体概况和PTEN缺失对酪氨酸的影响 激酶信号转导将鉴定PTEN的新作用，提供因PTEN缺失而改变的候选磷蛋白， 揭示了信号通路之间的新联系。IGF-IR在大多数人乳腺中表达， 癌症和治疗性IGF-IR抑制剂正在开发中。鉴定PTEN缺失对肿瘤细胞增殖的影响。 IGF-IR信号传导和对IGF-IR靶向治疗的敏感性将揭示PTEN的新功能， 确定PTEN状态是否是对治疗反应的生物标志物。反过来，这些集体发现将 允许优化靶向IGF-IR和PI 3 K途径的疗法。本报告提出的研究将 在范德比尔特-英格拉姆癌症中心进行，其设施和中心非常适合 分子、遗传、蛋白质组和活体动物成像分析。该机构还 提供广泛的教学活动和职业发展机会，以加强年轻人的培训。 investigators.上述研究将为我提供一个丰富的环境中加强科学训练， 合作和跨学科研究，以促进增长和独立。我近期的职业目标 是获得一个独立的，终身制的，助理教授的职位，建立自己的 实验室和研究团队，长期目标是建立一个额外的资助计划， 基于机制的转化癌症研究。

Project Summary/Abstract The objective of these studies is to understand the effects of loss of the tumor suppressor Phosphatase and Tensin homolog deleted on chromosome 10 (PTEN) in breast cancer, and the effects of PTEN functions on tyrosine kinase signaling. Aberrant activation of the phosphatidylinositol-3 kinase (PI3K) pathway is one of the most frequent molecular alterations in human cancer, most often by loss of expression or loss-of-function mutations in PTEN. PTEN acts as a lipid phosphatase downstream of PI3K to antagonize PI3K signaling, but PTEN protein phosphatase activity has tumor suppressive effects which remain unresolved. PTEN deficiency results in activation of receptor tyrosine kinases (RTKs) including insulin-like growth factor-I receptor (IGF-IR), insulin receptor (InsR), and ErbB3/HER3, implicating PTEN in the modulation of signaling both upstream and downstream of PI3K. I therefore hypothesize that 1) the tumor suppressive effects of PTEN protein phosphatase activity involve direct dephosphorylation of oncoproteins including RTKs, and 2) PTEN loss sensitizes cancer cells to RTK inhibition. Results in support of hypothesis #1 would suggest that loss of PTEN not only increases PI3K pathway signaling, but also increases oncogenic signaling through protein-directed pathways that remain to be defined. In this case, PI3K inhibition may be insufficient to block the growth of PTEN-deficient tumors. Results in support of hypothesis #2 would offer PTEN loss as a biomarker of a patient subpopulation likely to benefit from RTK-directed therapy. To test these hypotheses, I propose the following Specific Aims: 1) To determine whether loss of PTEN modulates IGF-I, insulin, and HER3 receptor signaling; 2) To determine whether PTEN loss sensitizes to therapeutic inhibitors of IGF-IR, InsR, and HER3; 3) To discover phosphoprotein substrates of PTEN and the global effects of PTEN protein phosphatase activity on tyrosine kinase signaling. Global profiling of PTEN protein substrates and the effects of PTEN loss on tyrosine kinase signaling will identify novel roles of PTEN, offer candidate phosphoproteins altered by PTEN loss, and reveal new connections between signaling pathways. IGF-IR is expressed in the majority of human breast cancers, and therapeutic IGF-IR inhibitors are being developed. Identification of the effects of PTEN loss on IGF-IR signaling and sensitivity to IGF-IR-targeted therapies will reveal novel functions of PTEN, and determine whether PTEN status is a biomarker of response to therapy. In turn, these collective findings will allow the optimization of therapies targeting the IGF-IR and PI3K pathways. The studies proposed herein will be carried out at the Vanderbilt-Ingram Cancer Center, with facilities and centers ideally suited for the molecular, genetic, proteomic, and live animal imaging analyses involved in this research. This institution also provides extensive didactic activities and career development opportunities to enhance the training of young investigators. The above studies will provide me with enhanced scientific training in an environment rich with collaborations and interdisciplinary research to promote growth and independence. My immediate career goal is the acquisition of an independent, tenure-track, assistant professor faculty position to establish my own laboratory and research team, with the long-term goal of establishing an extramurally-funded program in mechanism-based translational cancer research.