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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：
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
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/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

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.

摘要