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Role of erbB3 in erbB2/neu-mediated Breast Cancer Development
Tumor Cell Biology V
Background: The receptor tyrosine kinase (RTK) erbB2/neu is a well-known oncogenic molecule that contributes to breast cancer cell proliferation, therapeutic resistance, and metastasis. Alteration of erbB2/neu has been shown to predict breast cancer patient outcome and response to various therapeutic regimens. The erbB3 receptor, which lacks kinase activity, is often co-expressed with erbB2 and may form a potent, growth promoting heterodimer. The biological roles of erbB3 in breast/mammary carcinogenesis and treatment response, however, are not well understood. Our studies of mice expressing the wild type rat c-neu transgene have demonstrated elevated expression of erbB3 in mammary tumors and tumor-derived cell lines. Stable and functional heterodimers comprised of endogenous mouse erbB3 and rat c-neu encoded by the transgene have been confirmed. Furthermore, down-regulation of erbB3 abrogated erbB2/neu-mediated breast cancer cell proliferation and tamoxifen resistance. These data indicate that up-regulation of erbB3 plays an important role in erbB2/neu-mediated tumorigenesis and may lead to a more aggressive phenotype. Hypothesis: The erbB3 receptor is vital for erbB2/neu-mediated mammary tumorigenesis, growth and therapeutic resistance. Specific Aims: 1) To investigate if elevated expression of erbB3 promotes erbB2/neu-mediated mammary tumor growth. We will study the effects of various erbB3 expression levels on erbB2 receptor activation, functional interaction between erbB2 and erbB3, tumor latency, histology, and metastasis using mammary tumors derived from wild type rat c-neu transgenic mice. 2) To define the role of erbB3 in erbB2/neu-mediated chemo-resistance. We will study if expression of erbB3 enhances or is required for erbB2/neu-mediated chemo-resistance and if this resistance involves PI-3K/Akt signaling or the cell cycle regulators, cdc2 and p21waf-1. 3) To determine if an anti-erbB3 blocking antibody (Ab) enhances Trastuzumab/Pertuzumab (erbB2-targeting Abs)-mediated growth inhibition or cell death. We will study RTK signaling, cell proliferation and apoptosis in vitro and in vivo following Ab treatment. Potential Outcomes and Benefits of the Research: These studies will focus on the role of erbB3 in anhancing erbB2-associated tumorigenesis and allow us to develop erbB3 as a target for anti-tumor therapies. Strategies targeting both erbB3 and erbB2 may be more efficacious than targeting erbB2 alone for breast cancer treatment.
The erbB receptor tyrosine kinase (RTK) family includes erbB1 (also known as EGFR), erbB2 (or HER2/neu), erbB3 and erbB4. Breast cancers with alterations of erbB2 are more aggressive and are typically more resistant to traditional therapeutic agents. Approaches targeting erbB2 for breast cancer treatments have shown efficacy, both alone and in combination with anti-cancer agents. The role of erbB3 in breast cancers is less well understood. Unlike erbB2, erbB3 lacks enzymatic activity and typically affects cancer cells via binding to erbB2. We have recently reported alterations of erbB3 in a transgenic mouse model that is genetically at-risk of mammary cancers because of enhanced transgenic erbB2 expression. We have shown frequent co-expression of erbB2 and erbB3, as well as functional interactions between these two receptors. In support of our data, recent studies suggest that erbB3 may play an important role in one-fourth to one-half of human breast cancers. These findings lead us to hypothesize that increased expression of erbB3 promotes erbB2-mediated breast cancer development and their associations may result in a more malignant phenotype. We propose three areas of study: 1) evaluation of the biologic function of erbB3 in erbB2-associated mammary tumors, 2) determination of whether erbB3 enhances or may be required for erbB2-induced chemo-resistance and the mechanism by which this occurs, and 3) determine if we can enhance cancer cell growth inhibition or death using novel agents targeting both erbB2 and erbB3, as compared to targeting either alone. These investigations will allow us to study the role of erbB3 in erbB2-associated breast cancer development and progression using a surrogate mouse model with demonstrated relevance to human breast cancer, and determine whether erbB3 is an important prognostic marker. We will also evaluate whether blockade of the erbB3 receptor induces anti-cancer effects and whether combinations of anti-erbB2 and anti-erbB3 antibodies are more efficacious than anti-erbB2 antibodies used singly. The data generated from these highly translational studies will provide us a basis to further develop erbB3 as a therapeutic target for breast cancer treatment.