Constitutive signaling by the Epidermal Growth Factor (EGF) Receptor (EGFR/c-ErbB1) frequently leads to increased tumor cell proliferation, motility, invasiveness and metastasis. Molecules that inhibit EGFR expression or activity are being assessed as potential antineoplastic agents.
One specific aim of this study is to identify which set of putative EGFR tyrosine kinase inhibitors has the highest specific activity.
A second aim i s to assess the effects of this EGFR kinase inhibitor(s) on the proliferation, motility and invasiveness of a panel of human mammary tumor cell lines. Such experiments will enable us to evaluate whether this compound(s) merits additional study as a potential treatment. EGFR is a member of the ErbB family of receptor tyrosine kinases, a family that includes three other members: Neu/ErbB2/HER2, ErbB3/HER3, and ErbB4/HER4. Ligands for these receptors are members of the EGF family of peptide hormones. Overexpression of at least two EGF family hormones, amphiregulin (AR) and transforming growth factor alpha (TGFalpha ), induces tumor cell proliferation, motility, invasiveness, and metastasis. Another EGF family hormone, Neuregulin-1 (NRG1), induces tumor cell differentiation and growth arrest. However, NRG1 activates a different set of ErbB family receptors than do AR and TGFalpha . Through collaborations, we have acquired cDNAs for three novel family hormones: NRG2, NRG3, and NRG4. Our third specific aim is to generate recombinant forms of these proteins. The fourth specific aim of this study is to identify which ErbB family receptors are activated by these hormones, using both human breast tumor cell lines and cell lines expressing defined combinations of receptors. Our fifth specific aim is to assess the effects of these hormones on breast tumor cell line proliferation, motility, and invasiveness. Finally, we will attempt to correlate the biological response of a given cell line to a given EGF family hormone to which ErbB family receptors are activated by that hormone in that cell line.
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