Controlling Homo- and Heterdimerization of ErbB Receptors Using Synthetic Ligands and Understanding the RTK Heterdimer Signaling Specificity in Breast Cancer
Final rept. 1 Aug 1999-31 Jul 2000
ARIAD INST FOR BIOMEDICAL RESEARCH CAMBRIDGE MA
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Coexpression of multiple ErbB receptors and EGF ligands in primary tumors complicates analysis of the cause and effect relationships between ErbB receptor expression and breast cancer. Since normal mammary epithelial cells express multiple ErbB receptors, it has not been possible to 1 determine whether ErbB receptors have distinct roles in epithelial transformation 2 understand the mechanisms by which distinct ErbB receptor dimers transform normal mammary epithelium. To evaluate the specific contributions of individual ErbB family members during transformation of the mammary epithelium, I combined a synthetic ligand-mediated controlled dimerization strategy and a modified cell culture approach to activate selected ErbB receptors in pre-formed acinar structures made up of growth-arrested polarized epithelial cells. I demonstrate that activation of ErbB2, but not ErbB1, within mammary acini resulted in disruption of the acinar organization and formation of large structures containing multiple acini-like units with filled luminal space similar to those observed in carcinoma in situ in vivo. Activation of ErbB2 was not sufficient to induce anchorage independence or migrationinvasion suggesting that ErbB2 homodimers induce early stages of carcinogenesis in culture. Our results also suggest, for the first time, that ErbB1 and ErbB2 homodimers differ in their ability to alter the polarized, growth-arrested organization of an epithelial acinus. These observations provide us with the means to study tumor progression in culture.
- Medicine and Medical Research