Suppression of EGFRvIII-mediated proliferation and tumorigenesis of breast cancer cells by ribozyme.

Abstract

EGFRvIII is a tumor specific, ligand-independent, constitutively active variant of the epidermal growth factor receptor. Its expression has been detected in many human malignancies including breast cancer. No detectable level of EGFRvIII has, however, been observed in adult tissues, including normal breast tissues. These unique features of the EGFRvIII make it an excellent target for biologically based therapies. We have designed and generated a tumor specific ribozyme targeted to EGFRvIII. This specific EGFRvIII ribozyme is able to effectively cleave EGFRvIII mRNA under physiological conditions in a cell-free system, but does not cleave wild-type EGFR and other EGF-family receptors. While expressing this EGFRvIII-ribozyme in breast cancer cells, EGFRvIII-ribozyme is capable of downregulating endogenous EGFRvIII expression at the mRNA and protein levels. Inhibition of proliferation was observed in EGFRvIII-ribozyme transfectants. In addition, downregulation of EGFRvIII in breast cancer cells significantly inhibited tumor growth in athymic nude mice. Furthermore, this ribozyme has no effect on EGF-family receptor expression or the proliferation of breast cancer cells, which do not express EGFRvIII but express wild-type EGFR and other EGF-family receptors. These results suggest that we have generated a tumor-specific, biologically functional ribozyme and further demonstrate that EGFRvIII plays a significant role in breast cancer cell proliferation. The ultimate goal of this approach is to provide a potential treatment for breast cancer by specifically targeting this receptor.