The initial link between E1A and tumor suppression in breast cancer was based on the observations that E1A could suppress the transformation phenotype of the neu-transformed NIH mouse 3T3 cells (10-12) by transcriptionally repressing the promoter of rat neu oncogene (9). HER-2 is amplified and overexpressed in approximately 30% human breast cancer patients with poor prognosis (29-31). Because the neu gene is a murine counterpart of the human HER-2 proto-oncogene, it was hypothesized that E1A could also repress HER-2 expression in human breast cancer. Indeed, both HER-2 protein and mRNA levels were reduced in HER-2-overexpressing breast cancer cell lines infected with an E1A-expressing adenovirus (Ad.E1A(+)) but not a mutant adenovirus (Ad.E1A(-)) in which E1A is deleted (13).
To test whether the E1A-mediated HER-2 repression affects the cell growth in cell model systems, both the high-HER-2 (e.g., MDA-MB-361 and SKBR3) and the low-HER-2-expressing (e.g., MDA-MB-435 and MDA-MB-231) breast cancer cell lines were infected with either Ad.E1A(+) or Ad.E1A(-) followed by a growth assay. We showed that Ad.E1A(+), but not Ad.E1A(-), could specifically inhibit the growth of the high-HER-2 breast cancer cells as compared with those with the low-HER-2 expression (32).
To demonstrate the efficacy of E1A in preclinical gene therapy settings, both Ad.E1A(+) and an E1A expression vector/liposome (3P-[N-(N' N dimethylaminoethyl) carbamoryl cholesterol [DCC]) complex (E1A/DCC) were used to assess the potential efficacy in an orthotopic, HER-2-overexpressing breast cancer model. MDA-MB-361 cells were transplanted into the mammary fat pads of female nu/nu mice. The mammary tumors become palpable usually about 45 d after implantation. Ad.E1A(+) or E1A/DCC was administered via intratumoral injection. Six months of E1A treatment (Ad.E1A(+) or E1A/DCC) resulted in suppression of tumor growth and prolonged survival (the mean survival was greater than 2 yr as opposed to less than 15 mo in the control groups). The Ad.E1A(+) treatment appeared slightly better than E1A/DCC treatment. Remarkably, no metastasis was found in intraperitoneal organs such as liver, intestine, spleen, and kidney (32). These results suggested that E1A possesses antimetastasis activity, which is reminiscent of a previous finding that showed no detectable metastasis in the E1A-treated mice bearing HER-2-overexpressing ovarian tumors (33). The suppression of mammary tumor by E1A correlated well with the expression of E1A and the reduced expression of HER-2 in these tumors (32). Thus, these data suggest the feasibility of an E1A-based gene therapy against HER-2-over-expressing breast cancer in vivo. Importantly, the subsequent toxicity studies conducted in immuno-competent mice showed only minimum side effect associated with the E1A gene therapy (34-36).
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