Novel Estrogen Receptor Phosphorylation Sites in Sensitivity/Resistance to SERMs

描述(申请人提供)：项目摘要。威廉姆斯博士目前的职业目标是在癌症的核受体信号领域确立自己的地位，长期目标是在癌症研究领域建立自己的职业生涯，专注于信号转导途径之间的串扰，因为它与癌症中的细胞信号有关。结合他之前在受体酪氨酸激酶信号传递方面的经验，拟议的研究计划将为威廉姆斯博士提供全面而全面的技能，以开启他作为一名独立科学家的职业生涯。除了实验室研究，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，他还将在国家和地方科学会议上介绍他的发现。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。 威廉姆斯博士将研究ER(在4个新发现的位点发生磷酸化)的治疗、预后和机制方面。初步结果表明，这些位点对ER(.这一建议假设，在ER(位于丝氨酸47、282、294和559)中发现的新的磷酸化位点将通过改变ER(转录活性)的机制影响他莫昔芬对他莫昔芬敏感和耐药的乳腺癌细胞的生长。目的1验证ER(S47、S282、S294和S559处的磷酸化)调节ER(转录活性、乳腺癌细胞在培养中的生长和体内肿瘤形成)的假说，目的2将确定调节ER(磷酸化)的激酶信号通路。AIM 3将从机制上阐述ER(丝氨酸S47、S282、S294、S559上的磷酸化)如何调节ER(对包括ER(二聚化、DNA结合和辅助调节因子招募)在内的配体的激活。目的4确定ER(丝氨酸47、282、294和559位的磷酸化)在原发乳腺肿瘤(IHC染色)中的临床意义。 关联性。对新的ER(磷酸化位点)的表征将有助于更好地理解乳腺癌治疗耐药的潜在机制。此外，这些研究可能通过靶向与耐药相关的激酶来改进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.