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The MUC1 mucin, found on the luminal surface of simple epithelial cells is upregulated and aberrantly glycosylated in many carcinomas particularly breast and ovarian. MUC1 expressed by normal mammary epithelial cells, carries core 2 glycans but in breast carcinomas the simple core 1 based glycans are added. The binding of the monoclonal antibody SM3 to its peptide epitope in the tandem repeat of MUC1 is blocked by the branched core 2 glycans found on MUC1 expressed by normal cells. Thus SM3 does not bind to MUC1 expressed by normal mammary epithelial cells but reacts with more than 90% of breast carcinomas, suggesting that the loss of at least some core 2 glycans is a very common event in breast carcinogenesis. To determine if the change in glycosylation observed in breast carcinomas confers an advantage to cancer cells, murine mammary carcinoma cell lines were developed that express MUC1 carrying core 2 or core 1 linked glycans. The in vivo growth rate in wild-type and nude mice were identical regardless of the O-glycosylation patterns. However, the tumors that grew out of wild-type mice lost most of their MUC1 expression. In contrast, in MUC1 transgenic mice, where expression of MUC1 was retained by the tumor, a striking difference in growth rate was observed. In these mice, cells expressing core 1 glycans grew significantly faster than cells expressing core 2 glycans. These data suggest that MUC1 transgenic mice are more tolerant to core 1 expressing tumors than to tumors expressing core 2.

The MUC1 epithelial mucin, which is overexpressed and aberrantly glycosylated in breast and other carcinomas, is also expressed on the apical surface of most normal glandular epithelial cells. Since clinical trials evaluating the efficacy of MUC1-based vaccines have been initiated in breast cancer patients, it is important to address the question of whether an effective immune response to the cancer associated mucin can be generated without inducing autoimmunity. Since non-classic cytotoxic T lymphocyte (CTL) responses to MUC1 have been reported, it is also relevant to examine the role of costimulatory molecules in the effective presentation of MUC1 based antigens. We have therefore looked at the effect of expressing B7.1 on the tumorigenicity of a MUC1 expressing mammary epithelial cell line (410.4) in a transgenic mouse expressing MUC1 on its normal glandular epithelial tissues. Coexpression of B7.1 with MUC1 in 410. 4 cells resulted in a dramatic inhibition of tumour growth which depended on the activity of CD4+ and CD8+ T cells. The epithelial tissues in the transgenic mice able to reject the B7.1, MUC1-expressing tumours showed no evidence of degeneration and the mice survived their normal life span. The results demonstrate that an immune response to the MUC1 antigen can be induced in MUC1 transgenic mice and that presentation of the antigen, whether directly or by cross-priming, is markedly enhanced by coexpression of B7.1.