Targeting HER-2/neu Overexpression By Suicide Ribozyme In Breast Cancer

摘要

Breast cancer represents a major cause of death for women in the United States. Overexpression of HER-2/neu oncogene was found in approximately 30% of breast tumor tissues and shown to be a marker indicating poor prognosis for breast cancer patients. HER-2/neu overexpression in cancer cells is also known to enhance cancer metastasis and to induce chemoresistance to certain anti-cancer drugs and repression of HER-2/neu expression reduces malignancy of the cancer cells. Therefore, HER-2/neu overexpression serves as an excellent target for development of breast cancer therapy. Ribozymes have been successfully used to control gene expression. We have designed a novel suicide ribozyme that will allow a gene of interest (such as a toxin gene) to be expressed specifically in the HER-2/neu-overexpressing breast cancer cells, and therefore, will kill only the HER-2/neu-overexpressing cells. This final report describes the progress in the following specific aims: (1) Design of the suicide ribozyme and proof of concept in vitro; (2) Proof of concept in vivo: a reporter gene regulated by the suicide ribozyme will be expressed only in cells overexpressing HER-2/neu mRNA. (3) Application of concept in vivo: a toxin gene regulated by the suicide ribozyme will preferentially inhibit the growth of breast cancer cells that overexpress HER-2/neu. During the last funding period (9/1/97 - 8131198), we have tested our suicide ribozymes in breast cancer cell lines that express either high or low level of HER-2/neu mRNA. Although we have not obtained the optimal suicide ribozyme that would consistently show a preferential expression in HER-2/neu overexpressors, our alternative approach using a HER-2/neu antisense iron responsive element has yielded an encouraging result which may lead to a potential gene therapy treatment a against HER-2/neu- overexpressin breast cancer cells.