THE TUMOR SUPPRESSION ACTIVITY OF E1A IN HER-2 NEU-OVEREXPRESSING BREAST-CANCER/

The HER-2/neu proto-oncogene is frequently amplified or overexpressed in human breast and ovarian cancers, and is significantly correlated w ith shorter survival, We have previously reported that the adenovirus type 5 early region 1A (E1A) gene product can repress HER-2/neu overex pression by repressing HER-2/neu promoter activity, and suppress the t umorigenic potential of HER-2/neu-overexpressing ovarian cancer cells, To examine E1A tumor suppressor function in breast cancer, we transdu ced E1A in vitro by adenovirus into both HER-2/neu-overexpressing and low expressing human breast cancer cell lines, In HER-2/neu-overexpres sing cells, E1A greatly inhibited tumor cell growth in vitro, However, in HER-2/neu low expressing cancer cell lines, E1A had no significant effect on cell growth in culture medium, To test the therapeutic effi cacy of E1A, we used both adenovirus-mediated and cationic liposome-me diated E1A gene delivery systems in an orthotopic breast cancer animal model, An advanced breast cancer model was established by inoculation of HER-2/neu-overexpressing human breast cancer cells in mammary fat pad and treated by local injections of either replication-deficient ad enovirus expressing EIA, Ad.E1A(+) or a liposome-E1A DNA complex, As c ontrols, mice bearing tumors were also treated with Ad.E1A(-) which is virtually the same adenovirus as Ad.E1A(+) except that EIA is deleted , a liposome-E1A frame-shift mutant DNA complex, or just PBS, In mice bearing a HER-2/neu-overexpressing breast cancer cell line, EIA delive red either by adenovirus or liposome significantly inhibited tumor gro wth and prolonged mouse survival compared with the controls, In fact, 60-80% of E1A-treated mice lived longer than 2 years versus only 0-20% of control mice (P<0.05), Western blot analysis showed that E1A prote in was expressed in tumor tissue and immunohistochemical analysis show ed that HER-2/neu p185 protein expression was suppressed, Taken togeth er, our results indicated that both adenovirus and cationic liposome d elivery systems were effective in transfering EIA gene for tumor suppr ession in a HER-2/neu-overexpressing breast cancer model.