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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23万名女性被诊断患有乳腺癌，近4万名女性将死于乳腺癌