Expression of the transmembrane
isoform of
Mucin 1 (MUC1/TM) in an aggressive murine mammary
tumor line, DA-3, does not alter
tumor development and
metastasis, leading to death of the host. However,
tumor cells expressing a secreted
isoform of MUC1 (MUC1/sec) fail to develop
tumors in immunocompetent mice. The rejection of MUC1/sec-expressing
tumor cells is immunologically mediated, as, initially, innate cells and, ultimately, T cells are required. After gene array analysis, and confirmation at the
protein level, it was discovered that MUC1/sec-expressing
tumor cells (DA-3/sec) have a significant reduction in expression of
urokinase-type plasminogen activator (uPA) relative to the parental
tumor line and
tumor cells expressing MUC1/TM. The
serine protease uPA has been found to be involved in growth-promoting signaling, angiogenesis, and induction of matrix remodeling leading to
metastasis. Although the
tumor-promoting
Stat3 transcription factor was unaltered in these
tumor cells, the
tumor-suppressive and IFN-responsive
signal transducer and activator of transcription 1 (Stat1) is dramatically up-regulated in DA-3/sec cells. In addition, treatment of various murine and human cell lines with
conditioned medium containing MUC1/sec results in up-regulation of Stat1. DA-3/sec
tumor cells are also sensitized to the antiproliferative effects of IFN-gamma. Furthermore, transfection of the Stat1 gene into DA-3
tumor cells leads to a down-regulation of uPA and delays
tumor progression. Thus, Stat1 up-regulation in DA-3/sec cells seems to play a significant role in the mechanism(s) by which rejection of
tumor cells expressing MUC1/sec may be occurring.