PhosphoSer134 GR, TGF-β and 14-3-3-zeta cooperate to promote progression of Triple Negative Breast Cancer

PhosphoSer134 GR、TGF-β 和 14-3-3-zeta 合作促进三阴性乳腺癌的进展

基本信息

批准号：
10113561
负责人：
Carlos Jesus Perez Kerkvliet
金额：
$ 5.1万
依托单位：
UNIVERSITY OF MINNESOTA
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-04-01 至 2022-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10113561
关键词：
Accounting Address Advanced Malignant Neoplasm Antigens Behavior Biological Markers Biology Breast Cancer Cell Breast Cancer Model Breast Cancer Patient Breast Cancer cell line Breast cancer metastasis Cancer Biology Cell Survival Cellular Stress Clinical Complex Computational Biology Data Data Set Development Dexamethasone Disease Doctor of Medicine Doctor of Philosophy Epidermal Growth Factor Epidermal Growth Factor Receptor Estrogen Receptors Event Fostering Gene Expression Gene Expression Regulation Genes Genetic Transcription Glucocorticoid Receptor Human Hypoxia Immunocompromised Host Impairment In Vitro Instruction Learning Ligands Lung Neoplasms Malignant Neoplasms Mediating Metastatic Neoplasm to the Lung Modeling Modernization Mus Neoplasm Metastasis Oncogenes Oncogenic Pathway interactions Patient-Focused Outcomes Patients Pharmacology Phenotype Phosphorylation Phosphotransferases Progesterone Receptors Prognosis Protein Tyrosine Kinase Proteins Reactive Oxygen Species Receptor Protein-Tyrosine Kinases Regimen Regulation Research Research Personnel Research Training Role SH3 Domains Scaffolding Protein Scientist Serine Signal Pathway Signal Transduction Site Stimulus Stress Structure Surgeon Surgical Oncology Techniques Testing The Cancer Genome Atlas Therapeutic Time Training Transforming Growth Factor beta Transforming Growth Factor beta Receptors Tumor Weights Up-Regulation Xenograft Model Xenograft procedure advanced breast cancer base breast cancer progression cancer cell cancer subtypes cell motility cofactor cytokine genetic signature glucocorticoid receptor alpha glucocorticoid-induced orphan receptor improved in vivo interest knock-down malignant breast neoplasm migration mouse model mutant novel overexpression programs protein expression receptor receptor expression receptor function response src Homology Region 2 Domain steroid hormone receptor targeted treatment transcriptome transcriptome sequencing triple-negative invasive breast carcinoma tumor tumor progression

项目摘要

PROJECT SUMMARY/ABSTRACT Therapeutic options for triple-negative breast cancer (TNBC) are limited. This subtype of breast cancer (BC) lacks expression of molecules currently exploited for targeted therapy including steroid hormone receptors, estrogen receptor and progesterone receptor, as well as human epidermal growth factor 2 receptor. TNBC is the most aggressive, metastatic, and deadly form of BC, and it accounts for up to 40% of all BC cases. Notably, 15- 40% of TNBC patients express glucocorticoid receptor (GR). GR is part of the steroid hormone receptor superfamily and its functions in TNBC are poorly understood. GR proteins are heavily post-translationally modified via phosphorylation events. Phosphorylation of GR has a variety of effects on GR function, including altered interaction with cofactors and subsequent changes in the regulation of global gene expression. Specifically, we are interested in phosphorylation of GR on Ser134, a site that is uniquely induced by cellular stress stimuli but independently of ligand. Notably, phosphoSer134 GR is critical for the expression of PTK6, a protein tyrosine kinase that is implicated in advanced breast cancer phenotypes. Our preliminary data indicates that phosphoSer134 GR expression is greater in TNBC relative to other breast cancer subtypes. TGFβ is a cytokine associated with aggressiveness of TNBC. Recently, we discovered that TGFβ signaling leads to phosphorylation of GR on Ser134 and promotes its interaction with the scaffolding protein 14-3-3ζ. Understanding the basis of cooperation between TGFβ, GR and 14-3-3ζ and subsequent upregulation of PTK6, will allow us to target this signaling and transcriptional complex as a means to block tumor progression and metastasis. In Aim 1, we propose to test the requirement for 14-3-3ζ as potential driver of phosphoSer134 GR target gene regulation and cancer cell migration/invasion and survival in TNBC models. In Aim 2, we will demonstrate the oncogenic roles of PTK6 as driver of tumor progression to metastasis in vivo using mouse xenograft studies. The proposed research and training plans provide a rigorous program for successful completion of my M.D./Ph.D. degrees. Moreover, it will provide me with the fundamentals to become a successful academic surgeon-scientist.

项目概要/摘要三阴性乳腺癌（TNBC）的治疗选择有限。这种乳腺癌亚型（BC）。缺乏目前用于靶向治疗的分子的表达，包括类固醇激素受体，雌激素受体和孕激素受体以及人表皮生长因子2受体是TNBC。最具侵袭性、转移性和致命性的 BC 形式，占所有 BC 病例的 40%，值得注意的是，15- 40% 的 TNBC 患者表达糖皮质激素受体 (GR)，它是类固醇激素受体的一部分。人们对 GR 超家族及其在 TNBC 中的功能知之甚少。 GR 的磷酸化对 GR 功能有多种影响，包括改变与辅助因子的相互作用以及随后全局基因表达调控的变化。具体来说，我们对 Ser134 上 GR 的磷酸化感兴趣，这是一个由细胞独特诱导的位点。值得注意的是，磷酸化Ser134 GR 对于PTK6 的表达至关重要。我们的初步数据表明，与晚期乳腺癌表型有关的蛋白酪氨酸激酶。相对于其他乳腺癌亚型，磷酸化 Ser134 GR 在 TNBC 中的表达更高。最近，我们发现 TGFβ 信号传导会导致 TNBC 的侵袭性。 GR 在 Ser134 上的磷酸化并促进其与支架蛋白 14-3-3ze 的相互作用。了解TGFβ、GR和14-3-3ζ之间的合作基础以及随后PTK6的上调，将使我们能够靶向这种信号传导和转录复合物作为阻止肿瘤进展的手段在目标 1 中，我们建议测试 14-3-3 z 作为磷酸化Ser134 GR 的潜在驱动因素的要求。在目标 2 中，我们将研究 TNBC 模型中的靶基因调控和癌细胞迁移/侵袭和存活。使用小鼠证明 PTK6 作为肿瘤进展至转移驱动因素的致癌作用拟议的研究和培训计划为成功提供了严格的计划。此外，完成我的医学博士/博士学位将为我提供成功的基础。学术外科医生科学家。