Tissue-specific Expression of a Human Polymorphic Epithelial Mucin (MUC1) in Transgenic Mice

Abstract

The human MUC1 gene codes for the core protein of a mucin which is expressed by glandular epithelia and the carcinomas which develop from these tissues. The core protein is aberrantly glycosylated in cancers, and 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 potential use of mucin-reactive antibodies and mucin-based immunogens in cancer patients, a mouse model, expressing the MUC1 gene product PEM (polymorphic epithelial mucin) as a self antigen, would be extremely useful. To this end, we have developed transgenic mouse strains expressing the human MUC1 gene product in a tissue-specific manner. The TG4 mouse strain was established using a 40-kilobase fragment containing 4.5 kilobases of 5′ and 27 kilobases of 3′ flanking sequence. The TG18 strain was developed using a 10.6-kilobase SacII fragment from the 40-kilobase fragment; this fragment contained 1.6 kilobases of 5′ sequence and 1.9 kilobases of 3′ flanking sequence. Both strains showed tissue specificity of expression of the MUC1 gene, which was very similar to the profile of expression seen in human tissues. The antibody SM-3 is directed to a core protein epitope, which is selectively exposed in breast cancers and which shows a more restricted distribution on normal human tissues. It was established that the distribution of the SM-3 epitope of PEM in the tissues of the transgenic mice is similar to that seen in humans. The transgenic mouse strains described here should form the basis for the development of a preclinical model for the evaluation of PEM-based antigens and of antibodies directed to PEM in cancer therapy.