TISSUE-SPECIFIC EXPRESSION OF A HUMAN POLYMORPHIC EPITHELIAL MUCIN (MUC1) IN TRANSGENIC MICE

The human MUC1 gene codes for the core protein of a mucin which is exp ressed by glandular epithelia and the carcinomas which develop from th ese tissues. The core protein is aberrantly glycosylated in cancers, a nd some antibodies show specificity in their reactions with the cancer -associated mucin, which also contains epitopes recognized by T-cells from breast and pancreatic cancer patients. For evaluating the potenti al use of mucin-reactive antibodies and mucin-based immunogens in canc er patients, a mouse model, expressing the MUC1 gene product PEM (poly morphic epithelial mucin) as a self antigen, would be extremely useful . To this end, we have developed transgenic mouse strains expressing t he human MUC1 gene product in a tissue-specific manner. The TG4 mouse strain was established using a 40-kilobase fragment containing 4.5 kil obases of 5' and 27 kilobases of 3' flanking sequence. The TG18 strain was developed using a 10.6-kilobase SacII fragment from the 40-kiloba se fragment; this fragment contained 1.6 kilobases of 5' sequence and 1.9 kilobases of 3' flanking sequence. Both strains showed tissue spec ificity of expression of the MUC1 gene, which was very similar to the profile of expression seen in human tissues. The antibody SM-3 is dire cted to a core protein epitope, which is selectively exposed in breast cancers and which shows a more restricted distribution on normal huma n tissues. It was established that the distribution of the SM-3 epitop e of PEM in the tissues of the transgenic mice is similar to that seen in humans. The transgenic mouse strains described here should form th e basis for the development of a preclinical model for the evaluation of PEM-based antigens and of antibodies directed to PEM in cancer ther apy.