The human epithelial mucin, MUC1, is a large transmembrane glycoprotei
n that is expressed on most simple epithelia. It is overexpressed and
aberrantly glycosylated on many human epithelial tumors, including mor
e than 90% of human breast cancers, MUC1 is of interest as an immunoth
erapy target because patients with breast, ovarian, and pancreatic can
cers have T lymphocytes in their tumor-draining lymph nodes that can b
e induced to recognize and lyse MUC1-expressing tumor cells, We have p
roduced a transgenic mouse model that expresses the human MUC1 molecul
e on an inbred C57Bl/6 background to investigate the effect of endogen
ous expression of MUC1 on the ability of mice to generate antitumor im
munity to MUC1-expressing tumors, Transgenic mice expressed the human
transgene in a pattern and level consistent with that observed in huma
ns, Transgenic mice were tolerant to stimulation by MUC1 as evidenced
by the ability of MUC1-expressing tumor cells to grow in these mice, w
hereas MUC1-expressing cells were eliminated from wild-type mice, More
over, transgenic mice immunized with MUC1 peptides failed to exhibit i
mmunoglobulin class switching to the IgG subtypes, These data suggest
that endogenous expression of MUC1 protein by MUC1 transgenic mice ind
uces T-cell tolerance to stimulation by MUC1, The transgenic mice will
provide a useful model to investigate the mechanisms that regulate im
munological tolerance to tumor antigens and will facilitate the invest
igation of anti-MUC1 immunotherapy formulations.