Blocking HER-2-Mediated Transformation with a Dominant Negative Form of HER-3

摘要

Evidence now indicates that the interaction between HER-2 and HER-3 receptor kinases leads to the constitutive activation of HER-2/HER-3 heterodimers in breast cancer cells with HER-2 gene amplification, and HER-2/ HER-3 then potently activates multiple signal transduction pathways that are involved in mitogenesis. This also suggests that inhibition of the interaction between HER-2 and HER-3 may be an effective and unique strategy for blocking the actions of HER-2 in human breast cancer cells. Therefore, we constructed various retroviral expression vectors that code for a dominant negative form of HER-3 which inhibits the function of HER-2/HER-3. We used these dominant negative HER- 3 vectors in experiments to determine the effectiveness of dominant negative HER-3 for blocking HER-2/HER-3 activation and growth in culture and in vivo for different breast cancer cell lines. with HER-2 gene amplification. Dominant negative HER-3 was able to inhibit the activation of HER-2/HER-3 ana the proliferation of cells stimulated by heregulin (the ligand for HER-2/HER-3), as well as their growth factor-independent (i.e. autonomous) proliferation in culture, anchorage-independent growth in soft agarose, and tumor growth in vivo. Our work also suggested that stoichiometric considerations involving different mutant/wild-type receptor levels in cells may also be important for blocking HER-2/HER-3.