HER3 Signaling in Development and Cancer of the Breast

描述（由申请方提供）：受体酪氨酸激酶的ErbB家族包括EGFR、ErbB 2/HER 2、ErbB 3/HER 3和ErbB 4/HER 4。大量证据支持HER 2过表达在高达25%的乳腺癌中的因果作用。虽然HER 3缺乏内在激酶活性，但HER 3通常在过表达HER 2的乳腺癌中过表达。HER 2与HER 3的异源二聚化增加乳腺细胞的增殖、存活和转化。酪氨酸磷酸化的HER 3有效地参与磷脂酰肌醇-3激酶（PI 3 K）/Akt途径，从而增加肿瘤细胞增殖和存活。 HER 2抑制剂如单克隆抗体曲妥珠单抗和双重EGFR/HER 2酪氨酸激酶抑制剂（TKI）拉帕替尼目前已获批用于治疗HER 2过表达转移性乳腺癌。然而，许多具有HER 2基因扩增的乳腺癌不响应和/或最终逃脱曲妥珠单抗和拉帕替尼。我们的假设是：1）HER 2：HER 3异二聚体的信号传导对乳腺肿瘤发生至关重要，2）HER 3表达增强肿瘤细胞存活，使肿瘤对靶向HER 2的治疗产生耐药性。根据这些假设，在没有HER 3的情况下，HER 2阳性乳腺肿瘤的发生率和恶性程度较低，靶向HER 3的治疗性抗体可以预防或逆转曲妥珠单抗或拉帕替尼耐药。这些结果将支持开发靶向HER 3及其下游效应物的治疗，作为HER 2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来有条件地消除ErbB 3（内源性小鼠HER 3）表达，特别是在小鼠乳腺上皮细胞（MEC）。在目标1中，我们将确定HER 3/ErbB 3是否是乳腺上皮发育所必需的。我们将使用携带MEC特异性ErbB 3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HER 3/ErbB 3在未转化的MEC中的作用，这些MEC可能最终有助于转化。目的2中的实验将确定体内乳腺肿瘤发生是否需要HER 3/ErbB 3。我们将使用基因工程小鼠模型的HER 2驱动和HER 2非依赖性乳腺癌，以确定是否需要ErbB 3的形成和恶性进展。目标3将确定HER 3抑制（遗传和非遗传）是否使HER 2过表达乳腺癌细胞对抗HER 2治疗敏感。将用靶向HER 3的单克隆抗体联合拉帕替尼和曲妥珠单抗治疗携带HER 2过表达乳腺癌的小鼠。总之，本提案中概述的实验将提供必要的知识，以确定ErbB 3的选择性靶向是否可能是针对HER 2过表达乳腺癌以及不过表达HER 2的乳腺癌的高级治疗的替代选择。

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.