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: 10295759
• 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
• 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/10295759
• 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.

抽象的 乳腺癌复发仍然是淋巴结阳性患者的重大风险。乳腺癌茎或茎 - 像细胞（此处的BCSC）传播并逃避一线疗法，并解释了高死亡率 患有晚期内分泌疾病的患者。该提议的目的是定义信号 推动内分泌耐药性BCSC的出现和扩展的途径，目的是阻止 表观遗传事件是针对该肿瘤细胞种群的。填补这一知识差距将铺平道路 为了阻止BCSC并确保长期无疾病生存的干预措施。我们确定了染色质 - 相关的，类固醇受体（SR）转录核心节PELP1作为BCSC膨胀的介体。利用 质谱法，我们确定了类固醇受体共激活剂3，SRC-3（也称为AIB1），是一种新型 与核PELP1相对于细胞质的优先相互作用。值得注意的是，PELP1增加了 BC细胞中的SRC-3，而SRC-3敲低阻断了PELP1诱导的BCSC膨胀，这表明必不可少 BCSC产物中活性PELP1/SRC3复合物的作用。在后续研究中，我们发现细胞质 PELP1促进了Thr24和Ser857上SRC-3的磷酸化。他人的工作已经实施了SRC-3 乳腺癌转移的PSER857作为双功能激酶/磷酸酶的关键底物 PFKFB4。在相关工作中，我们表明PELP1形成了两种雌激素的组成型转录复合物 乳腺癌模型和患者肿瘤中的（ER）和孕激素（PR）受体； Pr-的脚手架行为 B，但不是孕酮，ER/PR/PELP1对基因的ER磷酸化和调节所必需 复合物，包括基因集对他莫昔芬的抗性很重要。在这里，我们假设 ER/PR/PELP1/SRC-3复合物募集并扩增介导的关键细胞质信号通路 染色质重塑和重编程类固醇受体（SR）调节所需的表观遗传事件 扩展耐药性BCSC种群所需的转录组。我们将在 乳腺癌模型以及以下具体目的： •识别PELP1/SRC-3激活的信号通路对于BCSC扩张和耐药性所必需的。 •确定PELP1/SRC-3复合物如何重编程SR转录组。 •确定PELP1/SRC-3/SR合作是否促进体内肿瘤发生。 当前的疗法主要抑制BC的增殖，但无法充分瞄准BCSC。了解 BCSC的PELP1/SRC-3/SR信号传导和可逆表观遗传调节的机制将揭示新颖的 针对该复合物（即ER以外）或下游信号的所需组件的疗法 分子并防止或扭转这一过程，从而显着影响 转移性乳腺癌。