HER3 Signaling in Development and Cancer of the Breast

乳腺癌发育和癌症中的 HER3 信号转导

基本信息

  • 批准号:
    7768523
  • 负责人:
  • 金额:
    $ 32.16万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2009
  • 资助国家:
    美国
  • 起止时间:
    2009-12-09 至 2014-11-30
  • 项目状态:
    已结题

项目摘要

DESCRIPTION (provided by applicant): The ErbB family of receptor tyrosine kinases includes EGFR, ErbB2/HER2, ErbB3/HER3 and ErbB4/HER4. Abundant evidence supports the causal role of HER2 overexpression in up to 25% of all breast cancers. While HER3 lacks intrinsic kinase activity, HER3 is often over-expressed in breast cancers that overexpress HER2. Heterodimerization of HER2 with HER3 increases proliferation, survival, and transformation of breast cells. Tyrosine-phosphorylated HER3 potently engages the phosphatidylinositol-3 kinase (PI3K)/Akt pathway, which increases tumor cell proliferation and survival. Inhibitors of HER2 such as the monoclonal antibody trastuzumab and the dual EGFR/HER2 tyrosine kinase inhibitor (TKI) lapatinib are currently approved for treatment of HER2-overexpressing metastatic breast cancer. However, many breast cancers with HER2 gene amplification do not respond and/or eventually escape trastuzumab and lapatinib. It is our hypothesis that 1) signaling by HER2:HER3 heterodimers is essential for mammary tumorigenesis, and 2) HER3 expression enhances tumor cell survival, rendering tumors resistant to therapies that target HER2. According to these hypotheses, HER2-positive breast tumors would be less frequent and less malignant in the absence of HER3, and therapeutic antibodies targeting HER3 may prevent or reverse trastuzumab or lapatinib resistance. These results would support the development of treatments targeting HER3 and its downstream effectors as alternative or adjuvant therapy for patients with HER2-positive breast cancers. We have designed experiments testing this hypothesis, using a novel genetic approach to conditionally eliminate ErbB3 (endogenous mouse HER3) expression specifically in the mammary epithelial cells (MECs) of mice. In Aim 1, we will determine if HER3/ErbB3 is required for development of the mammary epithelium. We will use mice harboring MEC-specific loss of ErbB3 to examine mammary glands at each stage of post-natal mammary gland development. These studies will reveal the role of HER3/ErbB3 in untransformed MECs that may ultimately contribute to transformation. Experiments in Aim 2 will determine if HER3/ErbB3 is required for mammary tumorigenesis in vivo. We will use genetically engineered mouse models of HER2-driven and HER2-independent breast cancers to determine if ErbB3 is required for their formation and malignant progression. Aim 3 will determine if HER3 inhibition (genetic and pharmacologically) sensitizes HER2 overexpressing breast cancer cells to anti-HER2 therapies. Mice bearing HER2-overexpressing breast cancers will be treated with monoclonal antibodies targeting HER3 in combination with lapatinib and trastuzumab. In summary, the experiments outlined in this proposal will provide the necessary knowledge with which to determine if selective targeting of ErbB3 might be an alternative choice for advanced therapy tailored to HER2-overexpressing breast cancers, as well as those that do not overexpress HER2. PUBLIC HEALTH RELEVANCE: These studies will provide a mechanistic understanding of how ErbB3 signaling influences complex biological events during mammary gland development and tumorigenesis. Experiments will determine if selective targeting of ErbB3 might be an alternative choice for advanced therapy tailored to HER2-overexpressing breast cancers, as well as those that do not overexpress HER2.
描述(申请人提供):ErbB受体酪氨酸激酶家族包括EGFR、ErbB2/HER2、ErbB3/HER3和ErbB4/HER4。大量证据支持HER2过度表达在高达25%的乳腺癌中的因果作用。虽然HER3缺乏内在的激酶活性,但在过度表达HER2的乳腺癌中,HER3经常过度表达。HER2和HER3的异位二聚可促进乳腺细胞的增殖、存活和转化。酪氨酸磷酸化的HER3有效地参与了磷脂酰肌醇-3激酶(PI3K)/Akt通路,从而促进了肿瘤细胞的增殖和存活。 HER2的抑制剂,如单抗曲妥珠单抗和双重EGFR/HER2酪氨酸激酶抑制剂(TKI)拉帕替尼,目前被批准用于治疗HER2过表达的转移性乳腺癌。然而,许多HER2基因扩增的乳腺癌没有反应和/或最终逃脱曲妥珠单抗和拉帕替尼。我们的假设是:1)HER2:HER3异源二聚体的信号在乳腺肿瘤的发生中是必不可少的;2)HER3的表达提高了肿瘤细胞的存活率,使肿瘤对针对HER2的治疗产生抵抗。根据这些假设,在没有HER3的情况下,HER2阳性的乳腺肿瘤将较少发生,恶性程度也较低,针对HER3的治疗性抗体可能防止或逆转曲妥珠单抗或拉帕替尼的耐药性。这些结果将支持针对HER3及其下游效应物的治疗方法的开发,作为HER2阳性乳腺癌患者的替代或辅助治疗。 我们设计了实验来验证这一假设,使用一种新的遗传方法有条件地消除ErbB3(内源性小鼠HER3)在小鼠乳腺上皮细胞(MECs)中的特异性表达。在目标1中,我们将确定HER3/ErbB3是否是乳腺上皮发育所必需的。我们将使用携带MEC特异性ErbB3缺失的小鼠来检查出生后乳腺发育的每个阶段的乳腺。这些研究将揭示HER3/ErbB3在未转化的微血管内皮细胞中的作用,最终可能有助于转化。AIM 2的实验将确定HER3/ErbB3是否是体内乳腺肿瘤发生所必需的。我们将使用HER2驱动和HER2非依赖性乳腺癌的基因工程小鼠模型来确定ErbB3是否是它们形成和恶性进展所必需的。目的3将确定HER3抑制(遗传和药物)是否使HER2过表达的乳腺癌细胞对抗HER2治疗敏感。携带HER2过表达乳腺癌的小鼠将接受针对HER3的单抗与拉帕替尼和曲妥珠单抗联合治疗。总之,本提案中概述的实验将提供必要的知识,以确定选择性靶向ErbB3是否可能成为针对HER2过度表达的乳腺癌以及那些不过度表达HER2的乳腺癌的高级治疗的替代选择。 公共卫生相关性:这些研究将提供对ErbB3信号如何在乳腺发育和肿瘤发生过程中影响复杂生物事件的机械性理解。实验将确定选择性靶向ErbB3是否可能是针对HER2过度表达的乳腺癌和那些不过度表达HER2的乳腺癌的高级治疗的替代选择。

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 }}

Rebecca Sara Cook其他文献

Rebecca Sara Cook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('Rebecca Sara Cook', 18)}}的其他基金

In Situ Albumin Binding siRNAs for Triple Negative Breast Cancer Tumor Penetration and Molecularly Targeted Therapy
原位白蛋白结合 siRNA 用于三阴性乳腺癌肿瘤穿透和分子靶向治疗
  • 批准号:
    10596246
  • 财政年份:
    2021
  • 资助金额:
    $ 32.16万
  • 项目类别:
In Situ Albumin Binding siRNAs for Triple Negative Breast Cancer Tumor Penetration and Molecularly Targeted Therapy
原位白蛋白结合 siRNA 用于三阴性乳腺癌肿瘤穿透和分子靶向治疗
  • 批准号:
    10737831
  • 财政年份:
    2021
  • 资助金额:
    $ 32.16万
  • 项目类别:
In Situ Albumin Binding siRNAs for Triple Negative Breast Cancer Tumor Penetration and Molecularly Targeted Therapy
原位白蛋白结合 siRNA 用于三阴性乳腺癌肿瘤穿透和分子靶向治疗
  • 批准号:
    10445055
  • 财政年份:
    2021
  • 资助金额:
    $ 32.16万
  • 项目类别:
In Situ Albumin Binding siRNAs for Triple Negative Breast Cancer Tumor Penetration and Molecularly Targeted Therapy
原位白蛋白结合 siRNA 用于三阴性乳腺癌肿瘤穿透和分子靶向治疗
  • 批准号:
    10661771
  • 财政年份:
    2021
  • 资助金额:
    $ 32.16万
  • 项目类别:
McI-1 Inhibitors for the treatment of Breast Cancer
用于治疗乳腺癌的 MCI-1 抑制剂
  • 批准号:
    8764759
  • 财政年份:
    2014
  • 资助金额:
    $ 32.16万
  • 项目类别:
HER3 Signaling in Development and Cancer of the Breast
乳腺癌发育和癌症中的 HER3 信号转导
  • 批准号:
    8196980
  • 财政年份:
    2009
  • 资助金额:
    $ 32.16万
  • 项目类别:
HER3 Signaling in Development and Cancer of the Breast
乳腺癌发育和癌症中的 HER3 信号转导
  • 批准号:
    8591383
  • 财政年份:
    2009
  • 资助金额:
    $ 32.16万
  • 项目类别:
HER3 Signaling in Development and Cancer of the Breast
乳腺癌发育和癌症中的 HER3 信号转导
  • 批准号:
    7998156
  • 财政年份:
    2009
  • 资助金额:
    $ 32.16万
  • 项目类别:
HER3 Signaling in Development and Cancer of the Breast
乳腺癌发育和癌症中的 HER3 信号转导
  • 批准号:
    8390510
  • 财政年份:
    2009
  • 资助金额:
    $ 32.16万
  • 项目类别:
McI-1 Inhibitors for the treatment of Breast Cancer
用于治疗乳腺癌的 MCI-1 抑制剂
  • 批准号:
    8593797
  • 财政年份:
    2003
  • 资助金额:
    $ 32.16万
  • 项目类别:

相似海外基金

心房細動に対するPulsed Field Ablationの組織創傷治癒過程を明らかにする網羅的研究
阐明房颤脉冲场消融组织伤口愈合过程的综合研究
  • 批准号:
    24K11201
  • 财政年份:
    2024
  • 资助金额:
    $ 32.16万
  • 项目类别:
    Grant-in-Aid for Scientific Research (C)
Targeted ablation of cerebral atherosclerosis using supramolecular self-assembly
利用超分子自组装靶向消融脑动脉粥样硬化
  • 批准号:
    24K21101
  • 财政年份:
    2024
  • 资助金额:
    $ 32.16万
  • 项目类别:
    Grant-in-Aid for Early-Career Scientists
遅延造影心臓MRIによる心房細動Ablation冷却効果の比較:28 vs. 31 mm Cryoballoon
使用延迟对比增强心脏 MRI 比较房颤消融冷却效果:28 毫米与 31 毫米 Cryoballoon
  • 批准号:
    24K11281
  • 财政年份:
    2024
  • 资助金额:
    $ 32.16万
  • 项目类别:
    Grant-in-Aid for Scientific Research (C)
CAREER: Heat Penetration Depth and Direction Control with Closed-Loop Device for Precision Ablation
职业:利用闭环装置控制热穿透深度和方向,实现精确烧蚀
  • 批准号:
    2338890
  • 财政年份:
    2024
  • 资助金额:
    $ 32.16万
  • 项目类别:
    Continuing Grant
Collaborative Research: RUI: Frontal Ablation Processes on Lake-terminating Glaciers and their Role in Glacier Change
合作研究:RUI:湖终止冰川的锋面消融过程及其在冰川变化中的作用
  • 批准号:
    2334777
  • 财政年份:
    2024
  • 资助金额:
    $ 32.16万
  • 项目类别:
    Continuing Grant
Collaborative Research: RUI: Frontal Ablation Processes on Lake-terminating Glaciers and their Role in Glacier Change
合作研究:RUI:湖终止冰川的锋面消融过程及其在冰川变化中的作用
  • 批准号:
    2334775
  • 财政年份:
    2024
  • 资助金额:
    $ 32.16万
  • 项目类别:
    Continuing Grant
InSPACE-VT_Development and Validation of Virtual Pace Mapping to Guide Catheter Ablation of Ventricular Tachycardia
InSPACE-VT_虚拟起搏测绘的开发和验证以指导室性心动过速导管消融
  • 批准号:
    EP/Z001145/1
  • 财政年份:
    2024
  • 资助金额:
    $ 32.16万
  • 项目类别:
    Fellowship
Collaborative Research: RUI: Frontal Ablation Processes on Lake-terminating Glaciers and their Role in Glacier Change
合作研究:RUI:湖终止冰川的锋面消融过程及其在冰川变化中的作用
  • 批准号:
    2334776
  • 财政年份:
    2024
  • 资助金额:
    $ 32.16万
  • 项目类别:
    Continuing Grant
MRI: Acquisition of a Laser Ablation - Inductively Coupled Plasma - Triple Quadrupole - Mass Spectrometer (LA-ICP-QQQ-MS) System For Research and Education
MRI:获取用于研究和教育的激光烧蚀 - 电感耦合等离子体 - 三重四极杆 - 质谱仪 (LA-ICP-MS/MS) 系统
  • 批准号:
    2320040
  • 财政年份:
    2023
  • 资助金额:
    $ 32.16万
  • 项目类别:
    Standard Grant
{{ showInfoDetail.title }}

作者:{{ showInfoDetail.author }}

知道了