Biological Effects of Activating Distinct ErbB Receptor Dimers in Polarized Growth Arrested Epithelia

摘要

ErbB family of receptor tyrosine kinases have been implicated in human breast cancers. In particular ErbB2 is over expressed in 25-35% of all breast cancers. We can selectively activate a particular receptor using a chimeric system and synthetic ligand. We combine this system with a three- dimensional cell culture system which allow cells to grow into mammary acini like structures in vitro. We have shown that activation of ErbB2 induces a change in cell polarity and re-initiates proliferation in 3D structures. Using these systems we have investigated how activation of ErbB2 disrupts epithelial cell polarity and disrupts proliferation control. In parboular we studied how the Par complex and Rho family of small GTPases regulate ErbB2-induced transformation of human mammary epithelial cells. We have shown that activated ErbB2 recruits Par6 and disrupts the par complex. We have also shown that interfering with the functional complex by expressing a Par6 mutant prevents ErbB2 from fully transforming mammary epithelial cells. In our efforts to understand the effect of deregulating the function of Par protein complex we made the unexpected observation that overexpression of Par6 induced growth- factor independent proliferation of mammary epithelial cells. Understanding how these proteins affect proliferation and cell polarity and their relationship to Erbb2 will identify diagnostic markers and drug targets to treat breast cancer.