Estrogen Receptor and NFkB Crosstalk in Breast Cancer

乳腺癌中的雌激素受体和 NFkB 串扰

基本信息

批准号：
10558646
负责人：
Jonna Frasor
金额：
$ 46.74万
依托单位：
UNIVERSITY OF ILLINOIS AT CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-12-04 至 2027-01-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10558646
关键词：
Address Aromatase Inhibitors Breast Cancer Cell Breast Cancer Model Breast Cancer Patient Breast Cancer cell line Cell Survival Cells Cellular Stress Combined Modality Therapy Data Development Diagnosis Disease Disease Progression Drug Tolerance Drug resistance Estrogen Receptor alpha Estrogen Receptors Event Funding Genetic Growth Human Immunocompetent Immunocompromised Host In Vitro Link Mammary Neoplasms Mediating Mus NF-kappa B Neoadjuvant Therapy Neoplasm Metastasis Organoids Outcome Pathway interactions Patients Phenotype Population Pre-Clinical Model Primary Neoplasm Proliferating Property Recurrence Recurrent disease Recurrent tumor Regulation Relapse Resistance Resistance development Risk Role Stress Survival Rate Tamoxifen Target Populations Testing Therapeutic Time Withdrawal Woman Work Xenograft procedure adjuvant endocrine therapy biological adaptation to stress cancer stem cell cell growth disorder risk genetic signature hormone therapy in vivo inhibitor insight malignant breast neoplasm mouse model neoplastic cell new combination therapies novel novel strategies pressure prevent relapse prevention relapse risk resistance mechanism response single-cell RNA sequencing small molecule inhibitor therapy resistant tumor tumor xenograft

项目摘要

More than 230,000 women in the US will be diagnosed with breast cancer and nearly 40,000 will die from the disease annually. The majority of breast tumors express estrogen receptor α (ER), found in ~70-80% of all cases. Women with ER+ tumors typically receive endocrine therapy (ET), such as aromatase inhibitors or tamoxifen (TAM). While initial survival rates are generally good, it is estimated that ~40% of ER+ tumors will relapse, with almost half of these recurring after completing the standard 5 years of adjuvant ET. This risk for late relapse suggests that in many cases a population of tumor cells can persist or tolerate ET agents, only to contribute to relapse once ET is completed. This conclusion is supported by several studies showing that 10 yr of ET is superior to 5 yr. In studying how early responses to the selective pressure of ET might contribute to ET-tolerance, we found that activation of NFB was a common event in ER+ breast tumors of patients treated with neo-adjuvant ET, as well as in ER+ breast cancer cell lines, patient derived organoids, and xenografts. This activation appears to be the result of an expansion of NFB+ breast cancer cells that can proliferate and persist despite ET treatment. Importantly, inhibiting NFB prevents relapse, as determined by the lack of regrowth of cells and tumors once TAM treatment is terminated. Moreover, we found that a gene signature derived from ET-tolerant cells was associated with high tumor grade and increased risk of relapse in patients with ER+ disease. Based on these findings, we hypothesize that the selective pressure of ET allows for the expansion of NFB+, ET- tolerant cell populations and that targeting these populations therapeutically will prevent relapse and disease progression. To test this, we propose three aims: Aim 1. To define ET-tolerant cell populations in ER+ breast cancer models; Aim 2. To determine the mechanism of NFB regulation and action in ET-tolerance; and Aim 3. To investigate the consequences of targeting ET-tolerant cell populations. To address these aims, we will perform single cell RNA-seq on ET-treatment naïve preclinical models under the selective pressure of short-term ET and over time as adaptive resistance develops. We will then investigate the persistence of these populations in preclinical models of ET-resistance and validate our findings in human primary and metastatic tumors. We will also examine the hypothesis that NFB activity in ET-tolerant cells is a response to cellular stress caused by the selective pressure of ET, as well as a protective player in response to that cellular stress. In addition, we will use complementary genetic and small molecule inhibitors that inhibit the NFB pathway, as well as inhibitors of key NFB regulators and effectors, to test the role of ET-tolerant cells in relapse and disease progression, using both patient-derived tumors in immunocompromised mice and an immunocompetent mouse model. The successful completion of these aims will establish i) a novel role for NFB in promoting ET-tolerance and disease relapse of ER+ breast cancer, ii) mechanistic insight into the function of NFB in promoting ET tolerance, and iii) novel strategies to target ET-tolerant cells to prevent recurrence of ER+ breast cancer.

美国将有超过 230,000 名女性被诊断出患有乳腺癌，近 40,000 人将死于乳腺癌大多数乳腺肿瘤都表达雌激素受体 α (ER)，约占所有病例的 70-80%。患有 ER+ 肿瘤的女性通常接受内分泌治疗 (ET)，例如芳香酶抑制剂或他莫昔芬 (TAM)。虽然最初的生存率一般都不错，但估计约 40% 的 ER+ 肿瘤会复发，其中几乎一半的患者在完成标准 5 年辅助 ET 后复发，存在晚期复发的风险。表明在许多情况下，肿瘤细胞群可以持续存在或耐受 ET 药物，只是为了促进 ET 完成后复发。多项研究表明 ET 10 年后复发。优于 5 岁在研究对 ET 选择压力的早期反应如何有助于 ET 耐受性时，我们发现 NFκB 激活是接受新辅助治疗的 ER+ 乳腺肿瘤患者的常见事件 ET 以及 ER+ 乳腺癌细胞系、患者来源的类器官和异种移植物中都会出现这种激活。是 NF+B+ 乳腺癌细胞扩增的结果，尽管 ET 仍能增殖并持续存在重要的是，抑制 NFκB 可以防止复发，这取决于细胞再生的缺乏和一旦 TAM 治疗终止，我们发现了来自 ET 耐受性的基因特征。细胞与 ER+ 疾病患者的高肿瘤分级和复发风险增加相关。根据这些发现，我们认为 ET 的选择压力允许 NF+B+、ET- 的扩展耐受细胞群，并且针对这些细胞群进行治疗将预防复发和疾病为了测试这一点，我们提出了三个进展目标：目标 1. 定义 ER+ 乳腺中的 ET 耐受细胞群癌症模型；目标 2. 确定 ET 耐受中 NF+B 的调节和作用机制；为了研究针对 ET 耐受细胞群的后果，我们将实现这些目标。在短期的选择压力下对未经 ET 治疗的临床前模型进行单细胞 RNA 测序随着适应性抵抗力的发展，我们将调查这些种群的持续存在。我们将在 ET 抗性的临床前模型中验证我们在人类原发性和转移性肿瘤中的发现。还检验了这样的假设：ET 耐受细胞中的 NFκB 活性是对由 ET 引起的细胞应激的反应。此外，我们还将使用 ET 的选择性压力以及针对该细胞压力的保护性参与者。抑制 NFκB 通路的互补遗传和小分子抑制剂，以及关键抑制剂 NF+B 调节器和效应器，使用两者来测试 ET 耐受细胞在复发和疾病进展中的作用免疫功能低下的小鼠和免疫功能正常的小鼠模型中的患者源性肿瘤。这些目标的完成将确立 i) NF+B 在促进 ET 耐受和疾病复发方面的新作用 ER+ 乳腺癌的研究，ii) 对 NF+B 在促进 ET 耐受性中的功能的机制洞察，以及 iii) 新颖针对 ET 耐受细胞预防 ER+ 乳腺癌复发的策略。