Controlling Homo- & Heterodimerization of ErbB Receptors Using Synthetic Ligands and Understanding the RTK Heterodimer Signaling Specificity in Breast Cancer

摘要

ErbB family receptors have been strongly implicated in the pathogenesis of human breast cancer. Ligands that activate ErbB receptors can induce the formation of homodimers of individual ErbB family receptor and heterodimers involving two different family members. This combinatorial partnering of ErbB receptors has significantly complicated attempts to understand the biological activities of each ErbB receptor. It has not been possible to understand the relative contribution of each ErbB dimer towards mammary epithelial transformation or differentiation and morphogenesis since the mammary epithelial cells express all four members of the family. I plan to use a controlled dimerization strategy that uses synthetic ligands to regulate homo- or heterodimerzation of chimeric ErbB receptors fused to ligand binding domains. I have established that this synthetic ligand-mediated dimerization strategy can recapitulate a number of biochemical and biological functions of ErbB receptors in Rati fibroblasts. I have begun studies in a normal human mammary epithelial cell line, MCF-lOA. MCF-lOA cells require EGF for growth and can undergo undergo morphogenesis to form polarized structures referred to as acini (which resemble secretory mammary alveoli in vivo) when grown within a 3 dimensional matrix .1 have established that synthetic ligand mediated activation of ErbB receptors in MCF-1 0A cells can induce proliferation and also preliminary results suggests that ErbB 1 homodimers are not efficient in inducing proliferation in an EGF-independent manner.