Novel Estrogen Receptor Phosphorylation Sites in Sensitivity/Resistance to SERMs

描述（由申请人提供）：项目摘要。 威廉姆斯博士的近期职业目标是在癌症的核受体信号传导领域建立自己的职业生涯，长期目标是在癌症研究领域建立职业生涯，重点是信号转导通路之间的串扰，因为它涉及癌症的细胞信号传导。结合他以前在受体酪氨酸激酶信号传导方面的经验，拟议的研究计划将为威廉姆斯博士提供全面和综合的技能，以启动他作为独立科学家的职业生涯。除了实验室研究外，威廉姆斯博士还将参加研究焦点小组，与他们讨论相关的科学问题，并定期提交数据。此外，他将在国家和地方科学会议上介绍他的研究结果。杜兰癌症中心的设施将由威廉姆斯博士支配，终身教职员工的专业知识将帮助指导他的研究。 博士威廉姆斯将研究ER的治疗、预后和机制（4个新发现的位点的磷酸化）。初步结果显示这些位点对ER的转录活性有显著影响。该提议假设在ER中鉴定的新的磷酸化位点（在丝氨酸47、282、294和559处）将通过改变ER（转录活性）的机制影响他莫昔芬对他莫昔芬敏感和耐药乳腺癌细胞生长的作用。目的1将检验ER（在S47、S282、S294和S559处的磷酸化）调节ER（转录活性、培养物中乳腺癌细胞的生长和体内肿瘤形成）的假设。目的2将鉴定调节ER（磷酸化）的激酶信号传导途径。目的3将机械地解决ER（丝氨酸S47、S282、S294、S559处的磷酸化）如何调节ER（响应于包括ER（二聚化）、DNA结合和辅调节因子募集的配体的活化）。目的4将确定ER（丝氨酸47、282、294和559的磷酸化）在原发性乳腺肿瘤中的临床意义（IHC染色）。 本案无关 表征新的ER（磷酸化位点将导致更好地理解乳腺癌治疗耐药的潜在机制。此外，通过靶向与耐药相关的激酶，这些研究可能会改善乳腺癌患者的治疗方案。

DESCRIPTION (provided by applicant): Project Summary. Dr. Williams' immediate career goal is to establish himself in the field of nuclear receptor signaling in cancer, with a longer term goal of establishing a career in cancer research focusing on the cross talk between signal transduction pathways as it pertains to cellular signaling in cancer. In conjunction with his previous experience in receptor tyrosine kinase signaling, the proposed research plan will arm Dr. Williams with a well rounded and comprehensive skill set to launch his career as an independent scientist. In addition to laboratory research, Dr. Williams will participate in research focus groups, with which he'll discuss pertinent scientific issues, and present data regularly. Furthermore, he will present his findings at national and local scientific meetings. Tulane Cancer Center facilities will be at Dr. Williams' disposal, and the expertise of tenured faculty to help guide his research. Dr. Williams will study the therapeutic, prognostic and mechanistic aspects of ER( phosphorylation at 4 newly identified sites. Preliminary results show a dramatic impact of these sites on transcriptional activity of ER(. This proposal hypothesizes that novel phosphorylation sites identified in ER( (at serines 47, 282, 294, and 559) will impact tamoxifen effects on growth of tamoxifen-sensitive and -resistant breast cancer cells through mechanisms that alter ER( transcriptional activity. Aim 1 will test the hypothesis that ER( phosphorylation at S47, S282, S294, and S559 regulates ER( transcriptional activity, growth of breast cancer cells in culture, and in vivo tumor formation, Aim 2 will identify the kinase signaling pathways that regulate ER( phosphorylation. Aim 3 will mechanistically address how ER( phosphorylation at serines S47, S282, S294, S559 regulates ER( activation in response to ligand including ER( dimerization, DNA binding and coregulator recruitment. Aim 4 will ascertain the clinical significance of ER( phosphorylation at serine 47, 282, 294, and 559 in primary breast tumors (IHC staining). Relevance. Characterization of novel ER( phosphorylation sites will lead to a better understanding of the mechanisms underlying therapeutic resistance in breast cancer. Furthermore these studies may lead to improved therapeutic regimens for breast cancer patients, by targeting kinases associated with resistance.