The Roles of MUC1 and EGFR in Breast Cancer Progression and Mammary Lactation

Abstract

The relationship between MUC1 and EGFR has been characterized by our lab to be highly tumorigenic. A peptide therapeutic was developed in our lab to block the cytoplasmic interaction of MUC1 and EGFR by competing with the EGFR-binding domain of MUC1. The peptide, PMIP, reduced invasion and proliferation in vitro and reduced tumor growth and metastasis in vivo. These studies demonstrated the potency of MUC1/EGFR interactions in tumor progression, and we sought to explore this concept further. We wanted to clarify a mechanism by which MUC1 and EGFR together drive breast cancer metastasis, and we identified c-Met as a mediator of MUC1 and EGFR-driven cell motility. In two separate assays, we demonstrated that c-Met activity was necessary for MUC1 and EGFR to promote migration and invasion. In addition, we wanted to identify the role of EGFR membrane localization in membrane identity and tumor initiation. We established several EGFR localization mutants to compare to wild-type basolateral EGFR and we performed proof-of-concept experiments to show that these mutants will be useful in future studies. Finally, we studied the effect of MUC1 and EGF loss on tissue architecture and function in the lactating mammary gland. EGF is the primary ligand for EGFR during lactation, and MUC1 is highly expressed during this period of mammary development. In addition, it has been shown that EGFR and MUC1 interact at the apical cell surface of lactating mammary ducts, yet there is no link between lactation and tumor formation. We hypothesized that MUC1 and EGFR interaction may have a role in maintaining tissue architecture and lactation function in the mouse mammary gland. We found instead that the loss of MUC1 and EGF had no noticeable effect on lactation and did not result in tissue defects. These studies further clarified the relationship between MUC1 and EGFR in several different contexts, showing a role for their interaction in metastatic progression, and showing that their ablation has no effect in the lactating mammary gland. Future studies will elucidate the role of MUC1 and EGFR interaction in tumor initiation, and we have taken several steps in our studies toward that goal.