Transgenic MUC1 interacts with epidermal growth factor receptor and correlates with mitogen-activated protein kinase activation ill the mouse mammarygland

MUC1 is a large (>400 kDa), heavily glycosylated transmembrane protein that is aberrantly expressed on greater than 90% of human breast carcinomas and subsequent metastases. The precise function of MUC1 overexpression in tumo rigenesis is unknown, although various domains of MUC1 have been implicated in cell adhesion, cell signaling, and immunoregulation. Stimulation of the MDA-MB-468 breast cancer line as well as mouse mammary glands with epiderm al growth factor results in the co-immunoprecipitation of MUC1 with a tyros ine-phosphorylated protein of similar to 180 kDa, We have generated transge nic lines overexpressing full-length (MMF), cytoplasmic tail deleted (Delta CT), or tandem repeat deleted (Delta TR)-human MUC1 under the control of t he mouse mammary tumor virus promoter to further examine the role of MUC1 i n signaling and tumorigenesis, Immunoprecipitation experiments revealed tha t full-length transgenic MUC1 physically associates with all four erbB rece ptors, and co-localizes with erbB1 in the lactating gland. Furthermore, we detected a sharp increase in ERK1/2 activation in MUC1 transgenic mammary g lands compared with Mud null and wild-type animals. These results point to a novel function of increased MUC1 expression, potentiation of erbB signali ng through the activation of mitogenic MAP kinase pathways.