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

• 批准号: 10059182
• 负责人: Carol A Lange
• 金额: $ 48.82万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 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/10059182
• 关键词: ATAC-seq; Biological Markers; Breast; Breast Cancer Cell; Breast Cancer Model; Breast Cancer Treatment; Breast cancer metastasis; Cancer Patient; Cells; Chicago; Chromatin; Collaborations; Combined Modality Therapy; Complex; Cytometry; Data; Diagnosis; Disease; Disease Resistance; Disease-Free Survival; Endocrine; Ensure; Epigenetic Process; Estrogen Receptors; Estrogen Therapy; Estrogens; Event; Follow-Up Studies; Future; Gene Expression; Gene Expression Regulation; Genes; Genetic Transcription; Goals; Health; Hypoxia; Intervention; Knowledge; Lead; Link; Longevity; Lung; Mammary Neoplasms; Mass Spectrum Analysis; Mediating; Mediator of activation protein; Metabolic; Metabolism; Metastatic breast cancer; Metastatic to; 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; Protein Kinase; Receptor Signaling; Recurrence; 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

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.

摘要 乳腺癌复发仍然是淋巴结阳性患者的一个重大风险。乳腺癌干或干- 样细胞（本文中的BCSC）扩散并逃避一线疗法，并且导致了BCSC中的高死亡率。 晚期内分泌抵抗性疾病患者。本提案的目的是定义信令 驱动内分泌抗性BCSC出现和扩增的途径，目的是阻断 表观遗传事件来特异性地靶向该肿瘤细胞群体。填补这一知识空白将铺平道路 用于阻断BCSC并确保长期无病生存的干预。我们鉴定了染色质- 相关的类固醇受体（SR）转录辅助调节因子PELP 1作为BCSC扩增的介体。利用 通过质谱分析，我们鉴定了类固醇受体辅激活因子-3，SRC-3（也称为AIB 1），作为一种新的 与细胞质的相互作用优先于与细胞核的相互作用。值得注意的是，PELP 1增加了 SRC-3在BC细胞中的表达，而SRC-3敲低则阻断PELP 1诱导的BCSC扩增，这表明在BC细胞中， 活性PELP 1/SRC 3复合物在BCSC生长中的作用。在后续研究中，我们发现， PELP 1促进SRC-3在Thr 24和Ser 857上的磷酸化。其他人的工作表明SRC-3 pSer 857在乳腺癌转移中作为双功能激酶/磷酸酶的关键底物， PFKFB 4.在相关的工作中，我们发现PELP 1与雌激素和雌激素受体形成组成型转录复合物。 (ER)和孕激素（PR）受体在乳腺癌模型和患者肿瘤中的作用; PR- ER磷酸化和ER/PR/PELP 1对基因的调节需要B，而不是孕酮 复合物，包括对他莫昔芬耐药重要的基因组。在此，我们假设， ER/PR/PELP 1/SRC-3复合物募集并扩增介导细胞凋亡的关键细胞质信号通路。 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 扩增耐药性BCSC群体所需的转录组。我们将测试这个假设， 乳腺癌模型和以下具体目标： ·鉴定PELP 1/SRC-3激活的信号通路对于BCSC扩增和治疗抗性至关重要。 ·确定PELP 1/SRC-3复合物如何重编程SR转录组。 ·确定PELP 1/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。了解 PELP 1/SRC-3/SR信号传导机制和BCSC的可逆表观遗传调控将揭示新的 靶向该复合物所需组分（即，除ER以外）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。