Transforming growth factor α-dependent cancer progression is modulated by Muc1

Transforming growth factor a (TGF(i) is a potent inducer of cellular transformation, through its binding and activation of the epidermal growth factor receptor (EGFR). Previous studies in our laboratory showed that EGFR could also be affected by the glycoprotein MUC1, which inhibits ligand-stimulated degradation of EGFR in breast epithelial cell lines. To determine the effect of Muc1 expression on TGF alpha/EGFR-dependent breast transformation, we crossed the WAP-TGF alpha transgenic mouse model of breast cancer onto a Muc1-null background. We found that the loss of Muc1 expression dramatically affects mammary gland transformation and progression. Although 100% of WAP-TGF alpha/Muc1(+/+) mice form mammary-land tumors by 1 year, only 37% of WAP-TGF alpha/MUC1(-/-) form tumors by this time. This difference is also associated with a delay in onset, with a doubling of onset time observed in the WAP-TGF alpha/Muc1(-/-) compared with the WAP-TGF alpha/Muc1(-/-) mice. Analysis of signal transduction pathways revealed that activation of cyclin D1 expression is significantly suppressed in tumors derived from WAP-TGFot/Muc1(-/-) animals compared with those expressing Muc1. The loss of Muc1 expression also results in a significant inhibition in the formation of hyperplastic lesions during tumor progression. On the C57B1/6 inbred background, pulmonary lesions were observed in 28 of 29 WAP-TGF alpha/Muc1(+/+), animals (including one metastatic pulmonary adenocarcinoma and multiple perivascular lymphomas), although none were detected in the WAP-TGF alpha/Muc(-/-) animals. Together, these data indicate that Muc1 is an important modulator of TGF alpha-dependent tumor progression.