Targeting Oncogenic PELP1/SRC-3 Signaling Complexes in ER+ Breast Cancer

靶向 ER 乳腺癌中的致癌 PELP1/SRC-3 信号复合物

基本信息

批准号：
10301265
负责人：
Thu Ha Truong
金额：
$ 20.17万
依托单位：
UNIVERSITY OF MINNESOTA
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-01-01 至 2025-12-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10301265
关键词：
Accounting Adopted Aftercare Area Automobile Driving Binding Biological Biology Breast Breast Cancer Cell Breast Cancer Model Breast Cancer Patient Cell Compartmentation Cell Nucleus Cell Survival Cell model Chemoresistance Clinical Complex Cytometry Cytoplasm Data Development Disease Disease Progression Distant Metastasis Endocrine Enzymes Estrogen Receptors Estrogen receptor positive Event Family member Foundations Genes Genetic Transcription Goals Growth Growth Factor Health Human Biology Impairment K22 Award Link Mammary Neoplasms Mediating Mediator Metabolic Metabolic Pathway Metabolism Metastatic breast cancer Minority Groups Modeling Molecular NCOA3 gene Neoplasm Metastasis Nuclear Oncogenic Organoids Paclitaxel Pathway interactions Patient-Focused Outcomes Patients Personal Satisfaction Phenocopy Phenotype Phosphoric Monoester Hydrolases Phosphotransferases Population Progesterone Receptors Proliferating Publishing Recurrence Relapse Reporting Research Resistance Resistance development Role Scaffolding Protein Signal Pathway Signal Transduction Site Solid Steroid Receptors Tamoxifen Testing Therapeutic Woman Work Xenograft Model Xenograft procedure advanced disease breast cancer progression cancer cell cancer diagnosis cancer stem cell cancer survival candidate identification candidate validation career chemotherapy genetic signature hormone therapy improved in vitro Model in vivo knock-down malignant breast neoplasm mammary metabolic phenotype neoplastic cell novel predictive signature resistance mechanism self-renewal standard care stem stem cell biology stem cell expansion stem cell population stem cell survival targeted treatment therapeutic target therapy resistant transcriptome sequencing translational cancer research tumor tumor metabolism tumor progression

项目摘要

Project Summary Breast cancer is the most commonly diagnosed cancer in women, with estrogen receptor positive (ER+) breast cancers accounting for 75% of cases. Endocrine therapies directed at blocking ER action are highly effective; however, 40% of women with ER+ tumors develop resistance and progress to metastatic disease. ER+ tumors relapse late, and tumor cells can remain quiescent for years to decades. Progress in the treatment of metastatic breast cancer is limited by strategies that primarily target rapidly proliferating tumor cells. Contributing factors to advanced disease progression include breast cancer stem cells (CSC), which are poorly proliferative and exist as minority populations in therapy resistant tumors. We identified SRC-3 (steroid receptor [SR] co-activator 3) as a novel cytoplasmic binding partner of PELP1. Similar to SRC-3, PELP1 is an ER co-activator, and dynamically shuttles between the nucleus and cytoplasm to act as a nuclear co-activator and cytoplasmic scaffolding protein for growth factor and steroid receptors. PELP1 is primarily nuclear in normal breast, but increased cytoplasmic localization of PELP1 is an oncogenic event that promotes disease progression by unknown mechanisms. We showed PELP1/SRC-3 cytoplasmic complexes drive breast CSC phenotypes and genes associated with pro-survival in ER+ breast cancer models. SRC-3 inhibition disrupts complex formation and cytoplasmic PELP1-induced tumorspheres. Top candidates identified from RNA-seq analysis include PFKFB family members, which are bi-functional kinase/phosphatases that have roles in cancer metabolism and CSC biology. PFKFB3/-4 co-purified with PELP1/SRC-3 complexes; inhibition of PFKFB3/-4 blocked PELP1/SRC-3 complex formation and biology. Remarkably, PELP1/SRC-3 CSC biology is phenocopied in tamoxifen-resistant (TamR) and paclitaxel-resistant (TaxR) models. Herein, we hypothesize that PELP1/SRC-3 complexes amplify signaling inputs to PFKFB family members that mediate altered metabolic pathways required for resistant ER+ tumor cell populations. We will: 1) identify signaling pathways essential for PELP1/SRC-3 driven therapy resistance using mass cytometry, and 2) determine the therapeutic benefits of targeting PELP1/SRC-3/PFKFB complexes in vivo to block cancer progression and metastasis. Our long-term objectives are to identify non-ER therapeutic targets that can be developed as combination strategies to eliminate therapy resistant tumor cells in ER+ breast cancer. During the K22 award, we expect to define the molecular links between cancer cell metabolism and oncogenic events in breast cancer progression, metastasis, and examine the benefits of targeting this pathway to impair late recurrence. This proposal will provide a solid foundation for the candidate’s goal of moving towards translational cancer research during her transition to independence. Delineating the key players will fundamentally redefine standard care options to target therapy-resistant populations in ER+ breast cancer.

项目概要乳腺癌是女性最常诊断的癌症，雌激素受体阳性 (ER+) 乳腺癌占 75% 病例的癌症旨在阻断 ER 作用的内分泌疗法非常有效；然而，40% 患有 ER+ 肿瘤的女性会产生耐药性并进展为转移性疾病。复发较晚，肿瘤细胞可保持静止数年至数十年。乳腺癌受到主要针对快速增殖的肿瘤细胞的策略的限制。晚期疾病进展包括乳腺癌干细胞 (CSC)，其增殖能力较差且存在我们确定了 SRC-3（类固醇受体 [SR] 共激活剂 3）。作为 PELP1 的新型细胞质结合伴侣，与 SRC-3 类似，PELP1 是一种 ER 共激活剂，并且在细胞核和细胞质之间动态穿梭，充当核共激活剂和细胞质生长因子和类固醇受体的支架蛋白 PELP1 在正常乳腺中主要位于核内，但 PELP1 细胞质定位增加是一种致癌事件，可通过以下方式促进疾病进展我们发现 PELP1/SRC-3 细胞质复合物驱动乳腺 CSC 表型和 ER+乳腺癌模型中与促生存相关的基因抑制SRC-3会破坏复合物的形成。通过 RNA-seq 分析确定的最佳候选者包括细胞质 PELP1 诱导的肿瘤球。 PFKFB 家族成员，是双功能激酶/磷酸酶，在癌症代谢和 CSC 生物学。与 PELP1/SRC-3 复合物共纯化的 PFKFB3/-4 被阻断； PELP1/SRC-3 复合物的形成和生物学值得注意的是，PELP1/SRC-3 CSC 生物学在表型中得到了体现。在这里，我们欺负了 PELP1/SRC-3。复合物放大 PFKFB 家族成员的信号输入，介导改变所需的代谢途径对于耐药 ER+ 肿瘤细胞群，我们将：1) 确定 PELP1/SRC-3 必需的信号通路。使用质谱流式细胞术驱动治疗耐药性，2) 确定靶向治疗的治疗益处 PELP1/SRC-3/PFKFB 体内复合物可阻止癌症进展和转移。是为了确定非 ER 治疗靶点，这些靶点可以开发为联合策略以消除治疗在 K22 颁奖期间，我们期望定义 ER+ 乳腺癌中的分子联系。癌细胞代谢与乳腺癌进展、转移和检查中的致癌事件之间的关系该提案将为针对该途径减少晚期复发的益处提供坚实的基础。候选人在向独立过渡期间转向转化癌症研究的目标。界定关键参与者将从根本上重新定义标准护理选择，以针对治疗耐药性 ER+乳腺癌人群。