HER3 Signaling in Development and Cancer of the Breast

描述（由申请人提供）：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过表达在高达25%的乳腺癌中起因果作用。虽然HER3缺乏内在的激酶活性，但HER3在HER2过表达的乳腺癌中经常过表达。HER2和HER3的异源二聚化增加了乳腺细胞的增殖、存活和转化。酪氨酸磷酸化的HER3可参与磷脂酰肌醇-3激酶(PI3K)/Akt通路，从而增加肿瘤细胞的增殖和存活。

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.