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

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:
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

项目摘要

项目成果

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中文摘要
翻译
这个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
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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Development of a clinically relevant mouse model of ER+ breast cancer
  • 批准号:
    10442604
  • 项目类别:
  • 资助金额:
    $22.29万
  • 财政年份:
    2021
  • 负责人:
    Zhe Li
  • 依托单位:
Mechanism of LSD1 in breast cancer metastasis suppression
  • 批准号:
    10533313
  • 项目类别:
  • 资助金额:
    $37.29万
  • 财政年份:
    2020
  • 负责人:
    Zhe Li
  • 依托单位:
Mechanism of LSD1 in breast cancer metastasis suppression
  • 批准号:
    10308092
  • 项目类别:
  • 资助金额:
    $37.29万
  • 财政年份:
    2020
  • 负责人:
    Zhe Li
  • 依托单位:
Interplay of mammary luminal cells and environmental factors in establishing p53-deficient premalignant field
  • 批准号:
    10061564
  • 项目类别:
  • 资助金额:
    $37.48万
  • 财政年份:
    2017
  • 负责人:
    Zhe Li
  • 依托单位:
海外基金