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:
- 金额:$ 19.15万
- 依托单位:
- 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:
- 关键词:AddressAdenovirusesAdultAffectAllelesAnimal ModelAnimalsAppearanceBiogenesisBiologyBreast Cancer cell lineBreast Epithelial CellsCCND1 geneCCNE2 geneCell Cycle ArrestCell Cycle ProgressionCell LineageCellsCessation of lifeClinicalCyclin D1DNA Sequence AlterationDeletion MutationDependenceDevelopmentDiseaseESR1 geneEctopic ExpressionEngraftmentEnhancersEstrogen TherapyEstrogen receptor positiveEstrogensEventExhibitsFailureFemaleGenesGenetically Engineered MouseGoalsHematopoietic NeoplasmsHematopoietic SystemHumanHyperactivityImmune responseImmune systemIn VitroInjectionsKeratinKnockout MiceLaboratoriesLeadMalignant NeoplasmsMammary NeoplasmsMammary TumorigenesisMesenchymalMetastatic breast cancerMetastatic toMixed NeoplasmModelingMouse Mammary Tumor VirusMusMutateMutationOncogenicOrganoidsPathway interactionsPatientsPhenotypePhysiologic pulsePhysiologicalPrimary NeoplasmProcessRB1 geneRUNX1 geneRecurrenceResistance developmentRibosomesSignal TransductionStressStudy modelsSupplementationTP53 geneTestingTransplantationWomanXenograft Modelbasebreast tumorigenesiscancer cellcancer typecarcinogenesiscell typeclinically relevantconditional knockoutcyclin E2experiencehormone therapyhuman cancer mouse modelimprovedin vivoin vivo Modelinterestloss of function mutationmalignant breast neoplasmmouse modelneoplastic cellnovelpre-clinicalpromoterstandard caretooltranscription factortumor
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.
这个被提议的R21项目的目的是开发和验证一种新的、临床相关的小鼠模型
雌激素受体阳性(ER+)乳腺癌。大多数人类乳腺癌是ER+的,可以通过以下方法治疗
内分泌治疗。目前治疗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抵抗力;2)一些患者最终进展为ER+
转移性乳腺癌。可以忠实地概括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,目前的活体模型是
不够充分。更真实地建立ER+乳腺癌模型仍然是一个未得到满足的临床需求
生理环境。未能在动物(如小鼠)中准确地建立ER+乳腺癌模型可能是由于:
1)致癌事件没有针对正确的细胞来源;2)特定的致癌突变
与人类ER+有关的乳腺肿瘤很少在小鼠身上建模。考虑到这些因素,我们
最近开发了一种新的ER+乳腺癌小鼠模型,该模型基于一种独特的重复基因突变
在人类ER+乳腺肿瘤中发现,即功能丧失突变或雌激素/ER信号缺失-
相关转录因子基因RUNX1。该模型是基于导管内注射表达Cre的
角蛋白8启动子控制下的重组腺病毒(Ad-Cre)对携带K8启动子的雌性小鼠的作用
RUNX1和P53的条件性基因敲除Ad-K8-Cre诱导K8+细胞RUNX1和P53的缺失
乳腺上皮细胞(MECs)导致ER+核糖体高活性乳腺肿瘤的发生
生物发生和免疫反应,这也在人类RUNX1缺陷的ER+乳腺癌中观察到。
然而,由于Ad-K8-Cre靶向ER+和ER-腔微血管内皮细胞,由此产生的肿瘤表现为
ER+和Claudin-Low(即具有间叶样外观的肿瘤细胞)的特征,它是
不清楚混合肿瘤表型是否是由于它们不同的细胞来源(例如,ER+与ER-Lumina
MECs)和/或由于P53丢失(促进细胞命运可塑性)。我们假设为了使这一点
与人类ER+乳腺癌更具临床相关性的模型,可通过诱导RUNX1-
丢失及其协同致癌事件(即,不同于P53-丢失),在ER+腔MEC(即,
ER+乳腺癌的潜在细胞来源)。为了解决这一问题,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+腔亚系的Cre表达,
因此,乳腺肿瘤的发生只能从ER+的腔细胞开始。在目标2中,我们将测试致癌因素
影响Rb-E2F途径的事件(因为过度活跃的核糖体生物发生可能导致核糖体应激,
可能通过这一途径导致细胞周期停滞)会与RUNX1-Lost协同,导致ER+
来自腔内微血管内皮细胞的乳腺肿瘤。这种模式的成功开发将提供一种
为更好地了解ER+乳腺癌的生物学和治疗提供了宝贵的工具。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
数据更新时间:{{ journalArticles.updateTime }}
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
数据更新时间:{{ journalArticles.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ monograph.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ sciAawards.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ conferencePapers.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ patent.updateTime }}
Zhe Li其他文献
Zhe Li的其他文献
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
{{ truncateString('Zhe Li', 18)}}的其他基金
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
- 批准号:
10442604 - 财政年份:2021
- 资助金额:
$ 19.15万 - 项目类别:
Mechanism of LSD1 in breast cancer metastasis suppression
LSD1抑制乳腺癌转移的机制
- 批准号:
10533313 - 财政年份:2020
- 资助金额:
$ 19.15万 - 项目类别:
Mechanism of LSD1 in breast cancer metastasis suppression
LSD1抑制乳腺癌转移的机制
- 批准号:
10308092 - 财政年份:2020
- 资助金额:
$ 19.15万 - 项目类别:
Interplay of mammary luminal cells and environmental factors in establishing p53-deficient premalignant field
乳腺腔细胞和环境因素在建立 p53 缺陷癌前场中的相互作用
- 批准号:
10061564 - 财政年份:2017
- 资助金额:
$ 19.15万 - 项目类别:
Interplay of mammary luminal cells and environmental factors in establishing p53-deficient premalignant field
乳腺管腔细胞和环境因素在建立 p53 缺陷癌前场中的相互作用
- 批准号:
10303044 - 财政年份:2017
- 资助金额:
$ 19.15万 - 项目类别:
Impact of aging on prostate cancer with TMPRSS2-ETS gene fusion
TMPRSS2-ETS 基因融合衰老对前列腺癌的影响
- 批准号:
9203369 - 财政年份:2016
- 资助金额:
$ 19.15万 - 项目类别:
Impact of aging on prostate cancer with TMPRSS2-ETS gene fusion
TMPRSS2-ETS 基因融合衰老对前列腺癌的影响
- 批准号:
9353356 - 财政年份:2016
- 资助金额:
$ 19.15万 - 项目类别:
CRISPR/Cas9-based lineage tracing for fate mapping of cancer cells and stem cells
基于 CRISPR/Cas9 的谱系追踪用于癌细胞和干细胞的命运图谱
- 批准号:
9262180 - 财政年份:2016
- 资助金额:
$ 19.15万 - 项目类别:
Impact of aging on prostate cancer with TMPRSS2-ETS gene fusion
TMPRSS2-ETS 基因融合衰老对前列腺癌的影响
- 批准号:
10007618 - 财政年份:2016
- 资助金额:
$ 19.15万 - 项目类别:
Lineage tracing and clonal analysis of oral cancer initiating cells
口腔癌起始细胞的谱系追踪和克隆分析
- 批准号:
8889248 - 财政年份:2014
- 资助金额:
$ 19.15万 - 项目类别:
相似海外基金
cGAS-STING Pathway Targeting Replicative Adenoviruses with CD46 Tropism and AFP Promoter Conditional Replication Restriction for the Treatment of Hepatocellular Carcinoma
cGAS-STING 通路靶向具有 CD46 趋向性和 AFP 启动子的复制腺病毒条件性复制限制用于治疗肝细胞癌
- 批准号:
10436626 - 财政年份:2021
- 资助金额:
$ 19.15万 - 项目类别:
Glioma therapy with oncolytic adenoviruses and immunometabolic adjuvants
溶瘤腺病毒和免疫代谢佐剂治疗胶质瘤
- 批准号:
10557162 - 财政年份:2021
- 资助金额:
$ 19.15万 - 项目类别:
Molecular therapy of replication-competent adenoviruses targeting characteristic gene mutations found in mesothelioma
针对间皮瘤中发现的特征基因突变的具有复制能力的腺病毒的分子疗法
- 批准号:
21K08199 - 财政年份:2021
- 资助金额:
$ 19.15万 - 项目类别:
Grant-in-Aid for Scientific Research (C)
Glioma therapy with oncolytic adenoviruses and immunometabolic adjuvants
溶瘤腺病毒和免疫代谢佐剂治疗胶质瘤
- 批准号:
10330464 - 财政年份:2021
- 资助金额:
$ 19.15万 - 项目类别:
Structural characterization of nucleoprotein cores of human adenoviruses
人腺病毒核蛋白核心的结构表征
- 批准号:
9807741 - 财政年份:2019
- 资助金额:
$ 19.15万 - 项目类别:
Molecular biology and pathogenesis of fowl adenoviruses
禽腺病毒的分子生物学和发病机制
- 批准号:
41625-2013 - 财政年份:2018
- 资助金额:
$ 19.15万 - 项目类别:
Discovery Grants Program - Individual
The therapeutic strategies with augmented replications of oncolytic adenoviruses for malignant mesothelioma
溶瘤腺病毒增强复制治疗恶性间皮瘤的治疗策略
- 批准号:
18K15937 - 财政年份:2018
- 资助金额:
$ 19.15万 - 项目类别:
Grant-in-Aid for Early-Career Scientists
Molecular biology and pathogenesis of fowl adenoviruses
禽腺病毒的分子生物学和发病机制
- 批准号:
41625-2013 - 财政年份:2017
- 资助金额:
$ 19.15万 - 项目类别:
Discovery Grants Program - Individual
Exploring the effects of nutrient deprivation on T cells and oncolytic adenoviruses, in order to create immune activators for tumour therapy
探索营养剥夺对 T 细胞和溶瘤腺病毒的影响,以创造用于肿瘤治疗的免疫激活剂
- 批准号:
1813152 - 财政年份:2016
- 资助金额:
$ 19.15万 - 项目类别:
Studentship
Research on detection of novel adenoviruses by genetic methods
新型腺病毒的基因检测研究
- 批准号:
16K09118 - 财政年份:2016
- 资助金额:
$ 19.15万 - 项目类别:
Grant-in-Aid for Scientific Research (C)