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：
7998156
负责人：
Rebecca Sara Cook
金额：
$ 31.28万
依托单位：
VANDERBILT UNIVERSITY
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

来源：
https://reporter.nih.gov/project-details/7998156
关键词：
1-Phosphatidylinositol 3-Kinase Ablation Adjuvant Therapy Alternative Therapies Biological Breast Breast Cancer Cell Breast Cancer Model Cell Proliferation Cell Survival Cells Clinical Complex Development Distant Metastasis Drug resistance ERBB2 gene ERBB3 gene Epidermal Growth Factor Receptor Epithelial Cells ErbB Receptor Family Protein ErbB4 gene Event Gene Amplification Genetic Genetically Engineered Mouse Heterodimerization Homologous Gene Human Investigation Knowledge Lactation Malignant - descriptor Mammary Neoplasms Mammary Tumorigenesis Mammary gland Mediating Modeling Monoclonal Antibodies Mouse Mammary Tumor Virus Mus Outcome Pathway interactions Patients Pharmaceutical Preparations Phosphotransferases Pregnancy Premalignant Protein Tyrosine Kinase Proteins Puberty Resistance Role Signal Pathway Signal Transduction Staging Testing Therapeutic Therapeutic antibodies Trastuzumab Tyrosine Tyrosine Kinase Inhibitor design improved in vivo inhibitor/antagonist lapatinib malignant breast neoplasm mammary epithelium mammary gland development member mouse model neoplastic cell novel overexpression prevent public health relevance research study resistance mechanism response therapy development therapy resistant tumor tumor progression tumorigenesis

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（由申请人提供）：受体酪氨酸激酶的ErbB家族包括EGFR、ErbB2/HER2、ErbB3/HER3和ErbB4/HER4。大量证据支持 HER2 过度表达与高达 25% 的乳腺癌有关。虽然 HER3 缺乏内在激酶活性，但 HER3 在过度表达 HER2 的乳腺癌中通常过度表达。 HER2 与 HER3 的异二聚化可增加乳腺细胞的增殖、存活和转化。酪氨酸磷酸化的 HER3 有效参与磷脂酰肌醇 3 激酶 (PI3K)/Akt 通路，从而增加肿瘤细胞的增殖和存活。 HER2抑制剂，例如单克隆抗体曲妥珠单抗和双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/或最终逃避曲妥珠单抗和拉帕替尼的治疗。我们的假设是：1) HER2:HER3 异二聚体的信号传导对于乳腺肿瘤发生至关重要，2) HER3 表达可增强肿瘤细胞的存活率，使肿瘤对靶向 HER2 的疗法产生耐药性。根据这些假设，在没有 HER3 的情况下，HER2 阳性乳腺肿瘤的发生率会降低，恶性程度也会降低，而针对 HER3 的治疗抗体可能会预防或逆转曲妥珠单抗或拉帕替尼耐药性。这些结果将支持开发针对 HER3 及其下游效应子的治疗方法，作为 HER2 阳性乳腺癌患者的替代或辅助治疗。我们设计了实验来测试这一假设，使用一种新颖的遗传方法有条件地消除 ErbB3（内源性小鼠 HER3）的表达，特别是在小鼠乳腺上皮细胞 (MEC) 中。在目标 1 中，我们将确定乳腺上皮的发育是否需要 HER3/ErbB3。我们将使用具有 MEC 特异性 ErbB3 缺失的小鼠来检查产后乳腺发育各个阶段的乳腺。这些研究将揭示 HER3/ErbB3 在未转化的 MEC 中的作用，最终可能有助于转化。目标 2 中的实验将确定体内乳腺肿瘤发生是否需要 HER3/ErbB3。我们将使用 HER2 驱动型和 HER2 独立型乳腺癌的基因工程小鼠模型来确定 ErbB3 是否是其形成和恶性进展所必需的。目标 3 将确定 HER3 抑制（遗传和药理学）是否会使 HER2 过度表达的乳腺癌细胞对抗 HER2 疗法敏感。携带 HER2 过度表达乳腺癌的小鼠将接受针对 HER3 的单克隆抗体联合拉帕替尼和曲妥珠单抗的治疗。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 过度表达乳腺癌以及不过度表达 HER2 乳腺癌的先进疗法的替代选择。公共健康相关性：这些研究将从机制上理解 ErbB3 信号如何影响乳腺发育和肿瘤发生过程中的复杂生物事件。实验将确定选择性靶向 ErbB3 是否可能成为针对 HER2 过度表达乳腺癌以及不过度表达 HER2 乳腺癌的先进疗法的替代选择。