We know that pathogenesis of cancer begins as hyperplastic lesions, some of which progress to malignancy while other remain benign. The molecular features that differentiate lesions are largely unknown. This is in part due to lack of our understanding of the molecular mechanisms that initiate transformation of epithelial cells in vivo. Loss of growth control and disruption of epithelial architecture are thought to be earliest events in cancer. However, we do not understand how oncogenes coordinately deregulate growth control and architecture to initiate transformation of epithelial cells in vivo. Oncogenes of the ErbB receptor tyrosine kinase family can initiate transformation of epithelia in vivo. However, it has been a challenge to understand how different members of the ErbB family transform epithelial cells because they function by forming homo- and heterodimers amongst themselves, which complicates our ability to dissect out the role played by specific ErbB dimers. We have developed a novel method to control dimerization of ErbB receptors that will allow us to activate specific receptor dimers of choice in normal epithelial cells. We have also adapted a cell culture method to generate three-dimensional, polarized, growth-arrested epithelial cells that share several properties with cells lining the ducts in vivo. Combination of these two approaches provides us with novel and powerful tool to understand the molecular mechanisms by which ErbB receptors transform growth-arrested, polarized epithelial cells. Using our unique system, we will activate various combinations of ErbB receptor dimers to (1) investigate the ability of specific ErbB dimers to induce uncontrolled proliferation and loss of architecture in 3D mammary epithelial acini-like structures and identify the signaling pathways critical for this process (2) identify the mechanisms by which different ErbB homo- and heterodimers affect localization and function of proteins that regulate epithelial cell polarity, and (3) determine the relationship between the ability of ErbB dimers to disrupt cell polarity and their ability to re-initiate proliferation in growth-arrested, polarized epithelial cells. Of particular importance is our capability to uncover novel molecular mechanism involved in initiation of carcinoma and also to identify novel and specific targets for treating patients with ErbB-positive tumors.
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