Development of a clinically relevant mouse model of ER+ breast cancer
Development of a clinically relevant mouse model of ER+ breast cancer
批准号:
10290139
负责人:
Zhe Li
金额:
$19.15万
依托单位国家:
美国
项目类别:
财政年份:
2021
资助国家:
美国
项目状态:
已结题
起止时间:
2021-07-01 至 2023-06-30
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
中文摘要
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
用于雌激素受体阳性(ER)的乳腺癌。大多数人的乳腺癌是ER,可以用来治疗
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;2)一些患者最终进展为急诊室
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尚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相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,即雌激素/ER信号的功能丧失突变或缺失-
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)导致核糖体过度活跃的ER乳腺肿瘤
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同时针对ER和ER-腔内微血管内皮细胞,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),在内质网腔微血管内皮细胞(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,专门针对内质网腔亚系的Cre表达,
因此,乳腺肿瘤的发生只能从内质网腔细胞开始。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,
可能通过此途径导致细胞周期停滞)会与RUNX1-Lost协同,导致内质网
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。
英文摘要
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.
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