Development of a clinically relevant mouse model of ER+ breast cancer

ER乳腺癌临床相关小鼠模型的开发

基本信息

批准号：
10290139
负责人：
Zhe Li
金额：
$ 19.15万
依托单位：
BRIGHAM AND WOMEN'S HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-07-01 至 2023-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10290139
关键词：
Address Adenoviruses Adult Affect Alleles Animal Model Animals Appearance Biogenesis Biology Breast Cancer cell line Breast Epithelial Cells CCND1 gene CCNE2 gene Cell Cycle Arrest Cell Cycle Progression Cell Lineage Cells Cessation of life Clinical Cyclin D1 DNA Sequence Alteration Deletion Mutation Dependence Development Disease ESR1 gene Ectopic Expression Engraftment Enhancers Estrogen Therapy Estrogen receptor positive Estrogens Event Exhibits Failure Female Genes Genetically Engineered Mouse Goals Hematopoietic Neoplasms Hematopoietic System Human Hyperactivity Immune response Immune system In Vitro Injections Keratin Knockout Mice Laboratories Lead Malignant Neoplasms Mammary Neoplasms Mammary Tumorigenesis Mesenchymal Metastatic breast cancer Metastatic to Mixed Neoplasm Modeling Mouse Mammary Tumor Virus Mus Mutate Mutation Oncogenic Organoids Pathway interactions Patients Phenotype Physiologic pulse Physiological Primary Neoplasm Process RB1 gene RUNX1 gene Recurrence Resistance development Ribosomes Signal Transduction Stress Study models Supplementation TP53 gene Testing Transplantation Woman Xenograft Model base breast tumorigenesis cancer cell cancer type carcinogenesis cell type clinically relevant conditional knockout cyclin E2 experience hormone therapy human cancer mouse model improved in vivo in vivo Model interest loss of function mutation malignant breast neoplasm mouse model neoplastic cell novel pre-clinical promoter standard care tool transcription factor tumor

项目摘要

The purpose of this proposed R21 project is to develop and validate a novel, clinically relevant mouse model for estrogen receptor-positive (ER+) breast cancer. Most human breast cancers are ER+ and are treated by endocrine therapy. Current clinical challenges for treating ER+ breast cancer include: 1) some patients do not respond to or develop resistance to endocrine therapy; 2) some patients eventually progress to ER+ metastatic breast cancer. Animal models that can faithfully recapitulate the biology of ER+ breast cancer are essential for addressing these challenges in a preclinical setting. However, current in vivo models are inadequate. It remains an unmet clinical need to more faithfully model ER+ breast cancer under the physiological setting. The failure to model ER+ breast cancer faithfully in animals (e.g., mice) may be due to: 1) oncogenic events are not targeted to the correct cellular origin; 2) oncogenic mutations specifically associated with human ER+ breast tumors are rarely modeled in mice. Taking these into consideration, we recently developed a new mouse model for ER+ breast cancer based on a recurrent genetic mutation uniquely found in human ER+ breast tumors, i.e., loss-of-function mutation or deletion of an estrogen/ER signaling- related transcription factor gene, RUNX1. The model is based on intraductal injection of a Cre-expressing adenovirus (Ad-Cre) under the control of the Keratin 8 promoter (Ad-K8-Cre) to female mice carrying conditional knockout alleles of Runx1 and p53. Ad-K8-Cre-induced loss of RUNX1 and p53 in K8+ luminal mammary epithelial cells (MECs) led to development of ER+ mammary tumors with hyperactive ribosome biogenesis and immune responses, which are also observed in human RUNX1-deficient ER+ breast cancers. However, since Ad-K8-Cre targets both ER+ and ER- luminal MECs and the resulting tumors exhibited features of both ER+ and Claudin-low (i.e., tumor cells with mesenchymal-like appearance) cancers, it is unclear whether the mixed tumor phenotype is due to their different cellular origins (e.g., ER+ vs. ER- luminal MECs) and/or due to p53-loss (which promotes cell fate plasticity). We hypothesize that in order to make this model more clinically relevant to human ER+ breast cancer, it can be further improved by inducing RUNX1- loss and its cooperating oncogenic events (i.e., other than p53-loss) specifically in ER+ luminal MECs (i.e., the potential cellular origin of ER+ breast cancer). To address this, two Specific Aims are proposed. Aim 1 will focus on developing a new Ad-Cre tool to specifically target Cre expression to the ER+ luminal sublineage, so that mammary tumorigenesis is initiated only from ER+ luminal cells. In Aim 2, we will test if oncogenic events affecting the RB-E2F pathway (as hyperactive ribosome biogenesis may lead to ribosomal stress, which may cause cell cycle arrest via this pathway) would cooperate with RUNX1-loss, leading to ER+ mammary tumors from luminal MECs. The successful development of such model would provide an invaluable tool for better understanding the biology and therapy of ER+ breast cancer.

这个拟议的 R21 项目的目的是开发和验证一种新颖的、临床相关的小鼠模型用于雌激素受体阳性 (ER+) 乳腺癌。大多数人类乳腺癌为 ER+，可通过以下方法治疗：内分泌治疗。当前治疗 ER+ 乳腺癌的临床挑战包括：1) 一些患者不对内分泌治疗有反应或产生耐药性； 2）一些患者最终进展为ER+ 转移性乳腺癌。能够忠实再现 ER+ 乳腺癌生物学的动物模型是对于在临床前环境中应对这些挑战至关重要。然而，目前的体内模型是不足。在以下条件下更忠实地模拟 ER+ 乳腺癌仍然是一个未满足的临床需求生理环境。未能在动物（例如小鼠）中忠实地模拟 ER+ 乳腺癌可能是由于： 1) 致癌事件没有针对正确的细胞起源； 2）特异性致癌突变与人类 ER+ 乳腺肿瘤相关的模型很少在小鼠中进行建模。考虑到这些，我们最近开发了一种新的 ER+ 乳腺癌小鼠模型，该模型基于独特的复发性基因突变在人类 ER+ 乳腺肿瘤中发现，即雌激素/ER 信号传导功能丧失突变或缺失 - 相关转录因子基因RUNX1。该模型基于导管内注射表达 Cre 的角蛋白 8 启动子 (Ad-K8-Cre) 控制下的腺病毒 (Ad-Cre) 携带 Runx1 和 p53 的条件敲除等位基因。 Ad-K8-Cre 诱导 K8+ luminal 中 RUNX1 和 p53 丢失乳腺上皮细胞（MEC）导致核糖体过度活跃的 ER+ 乳腺肿瘤的发展生物发生和免疫反应，这也在人类 RUNX1 缺陷 ER+ 乳腺癌中观察到。然而，由于 Ad-K8-Cre 同时靶向 ER+ 和 ER- 管腔 MEC，因此产生的肿瘤表现出 ER+ 和 Claudin-low（即具有间质样外观的肿瘤细胞）癌症的特征，尚不清楚混合肿瘤表型是否是由于其不同的细胞起源（例如 ER+ 与 ER- luminal MEC）和/或由于 p53 缺失（促进细胞命运可塑性）。我们假设为了使这个模型与人类 ER+ 乳腺癌临床相关性更高，可以通过诱导 RUNX1- 进一步改进损失及其协同致癌事件（即，p53 损失除外），特别是在 ER+ 管腔 MEC 中（即， ER+乳腺癌的潜在细胞起源）。为了解决这个问题，提出了两个具体目标。目标1 将专注于开发一种新的 Ad-Cre 工具，专门针对 ER+ luminal 亚系的 Cre 表达，因此乳腺肿瘤的发生仅由 ER+ 管腔细胞启动。在目标 2 中，我们将测试是否致癌影响 RB-E2F 途径的事件（因为核糖体生物发生过度活跃可能导致核糖体应激，可能通过该途径导致细胞周期停滞）将与 RUNX1 丢失配合，导致 ER+ 来自管腔 MEC 的乳腺肿瘤。该模型的成功开发将为是更好地了解 ER+ 乳腺癌生物学和治疗的宝贵工具。