SRC-3/PELP1 complexes drive stem-like phenotypes in luminal breast cancer

SRC-3/PELP1 复合物驱动管腔乳腺癌中的干细胞样表型

基本信息

批准号：
10532137
负责人：
Carol A Lange
金额：
$ 48.01万
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：
2019-12-01 至 2024-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10532137
关键词：
ATAC-seq Biological Markers Breast Breast Cancer Cell Breast Cancer Model Breast Cancer Treatment Breast cancer metastasis Cancer Patient Cells ChIP-seq Chicago Chromatin Collaborations Combined Modality Therapy Complex Cytometry Cytoplasm Data Diagnosis Disease Disease Resistance Disease-Free Survival Endocrine Ensure Epigenetic Process Estrogen Receptors Estrogens Event Follow-Up Studies Future Gene Expression Gene Expression Regulation Genes Genetic Transcription Goals Health Hypoxia Intervention Knowledge Link Longevity Lung Mammary Neoplasms Mass Spectrum Analysis Mediating Mediator Metabolic Metabolism Metastatic breast cancer Modeling Mouse Mammary Tumor Virus NCOA3 gene Neoplasm Metastasis Nuclear Oncogenes Oncogenic Pathway interactions Patients Phenotype Phosphoric Monoester Hydrolases Phosphorylation Phosphotransferases Population Positive Lymph Node Process Progesterone Progesterone Receptors Proliferating Protein Kinase Receptor Signaling Recurrence Recurrent Malignant Neoplasm Resistance Resistance development Resolution Risk Role Signal Pathway Signal Transduction Signaling Molecule Specific qualifier value Steroid Receptors Stress Tamoxifen Target Populations Testing Time Transcription Coactivator Transgenic Mice Woman Work breast cancer progression cancer recurrence cancer stem cell chromatin remodeling epigenetic regulation hormone therapy in vitro Model in vivo innovation knock-down malignant breast neoplasm mortality mouse model neoplastic cell new therapeutic target novel overexpression prevent programs promoter protein complex recruit scaffold stem stem cells stem-like cell steroid hormone receptor targeted treatment therapy duration therapy resistant transcriptome transcriptome sequencing tumor tumor metabolism tumorigenesis

项目摘要

Abstract Breast cancer recurrence remains a significant risk among node-positive patients. Breast cancer stem or stem- like cells (BCSCs herein) disseminate and evade first-line therapies, and account for high mortality among patients with advanced endocrine-resistant disease. The objective of this proposal is to define the signaling pathways that drive the emergence and expansion of endocrine-resistant BCSCs, with the goal of blocking epigenetic events to specifically target this population of tumor cells. Filling this knowledge gap will pave the way for intervention that blocks BCSCs and ensures long-term disease-free survival. We identified the chromatin- associated, steroid receptor (SR) transcriptional coregulator, PELP1, as a mediator of BCSC expansion. Utilizing mass spectrometry, we identified the steroid receptor coactivator-3, SRC-3 (also known as AIB1), as a novel and preferential interactor with cytoplasmic relative to nuclear PELP1. Notably, PELP1 increased activation of SRC-3 in BC cells, while SRC-3 knockdown blocked PELP1-induced BCSC expansion, suggesting an essential role for active PELP1/SRC3 complexes in BCSC outgrowth. In follow-up studies, we found that cytoplasmic PELP1 promotes the phosphorylation of SRC-3 on Thr24 and Ser857. Work of others has implicated SRC-3 pSer857 in breast cancer metastasis as a key substrate of the bifunctional kinase/phosphatase known as PFKFB4. In related work, we showed that PELP1 forms constitutive transcriptional complexes with both estrogen (ER) and progesterone (PR) receptors in breast cancer models and patient tumors; a scaffolding action of PR- B, but not progesterone, was required for ER phosphorylation and regulation of genes by ER/PR/PELP1 complexes, including gene sets important for tamoxifen resistance. Herein, we hypothesize that ER/PR/PELP1/SRC-3 complexes recruit and amplify key cytoplasmic signaling pathways that mediate epigenetic events required for chromatin remodeling and reprogramming of steroid receptor (SR)-regulated transcriptomes required for expansion of therapy resistant BCSC populations. We will test this hypothesis in breast cancer models and in the following Specific Aims: • Identify PELP1/SRC-3-activated signaling pathways essential for BCSC expansion and therapy resistance. • Determine how PELP1/SRC-3 complexes reprogram SR transcriptomes. • Determine if PELP1/SRC-3/SR cooperation promotes tumorigenesis in vivo. Current therapies primarily inhibit BC proliferation, but fail to adequately target BCSCs. Understanding the mechanisms of PELP1/SRC-3/SR signaling and reversible epigenetic regulation of BCSCs will reveal novel therapies that target the required components of this complex (i.e. other than ER) or downstream signaling molecules and prevent or reverse this process, thus significantly impacting on the longevity of patients with metastatic breast cancer.

抽象的对于淋巴结阳性的乳腺癌干细胞或干细胞肿瘤患者来说，乳腺癌复发仍然是一个重大风险。类似细胞（此处为 BCSC）传播并逃避一线治疗，并导致高死亡率该提案的目的是定义信号传导。驱动内分泌耐药 BCSC 出现和扩张的途径，目的是阻断专门针对该肿瘤细胞群的表观遗传事件将为填补这一知识空白铺平道路。我们确定了阻止 BCSC 并确保长期无病生存的干预措施。相关的类固醇受体 (SR) 转录共调节因子 PELP1，作为 BCSC 扩张的介质。通过质谱分析，我们鉴定出类固醇受体辅激活剂-3，SRC-3（也称为 AIB1），作为一种新型值得注意的是，PELP1 增加了 PELP1 的激活。 BC 细胞中的 SRC-3，而 SRC-3 敲除可阻止 PELP1 诱导的 BCSC 扩增，这表明活性 PELP1/SRC3 复合物在 BCSC 生长中的作用在后续研究中，我们发现细胞质。 PELP1 促进 SRC-3 在 Thr24 和 Ser857 上的磷酸化，其他人的工作也涉及 SRC-3。 pSer857 在乳腺癌转移中作为双功能激酶/磷酸酶的关键底物在相关工作中，我们发现 PELP1 与两种雌激素形成组成型转录复合物。 (ER) 和孕酮 (PR) 受体在乳腺癌模型和患者肿瘤中的支架作用； ER 磷酸化和 ER/PR/PELP1 基因调节需要 B，但不需要孕酮复合物，包括对他莫昔芬耐药性重要的基因组。 ER/PR/PELP1/SRC-3 复合物招募并放大介导的关键细胞质信号传导途径类固醇受体 (SR) 调节的染色质重塑和重编程所需的表观遗传事件我们将在 BCSC 群体中验证这一假设。乳腺癌模型和以下具体目标： • 确定PELP1/SRC-3 激活的信号通路对于BCSC 扩张和治疗耐药至关重要。 • 确定PELP1/SRC-3 复合物如何重新编程SR 转录组。 • 确定PELP1/SRC-3/SR 合作是否促进体内肿瘤发生。目前的疗法主要抑制 BC 增殖，但未能充分靶向 BCSC。 PELP1/SRC-3/SR 信号传导机制和 BCSCs 可逆表观遗传调控将揭示新的机制针对该复合物所需成分（即除 ER 之外）或下游信号传导的疗法分子并阻止或逆转这一过程，从而显着影响患者的寿命转移性乳腺癌。