Interaction of the MUC1 Tumor Antigen and the Adenomatous Polyposis Coli Tumor Suppressor in Human Breast Cancer

摘要

This project was designed to analyze the effect of MUC1 and APC on two important signaling pathways in breast cancer, those mediated by Beta- catenin and the ErbB kinases. We present herein results indicating that loss of MUC1 corresponds to decreased total Beta-catenin levels in breast cancer cells; as this is accompanied by a reduction in the amount of Beta-catenin that lacks GSK3Beta-mediated phosphorylation, the destabilization of Beta-catenin after MUC1 loss occurs at least in part through the APC/GSK3Beta destruction complex. We also show that another APC-dependent pathway involving p53 might participate as well, since MUC1 loss correlates to increased p53 levels. Finally, we show that loss of MUC1 alters Beta-catenin dependent transcription, as well as demonstrating a novel link between expression of MUC1 and transcription of members of the ERK pathway downstream of the ErbB kinases. These transcriptional changes are correlated to alterations in oncogenic events, further supporting the idea that MUC1 and APC are integral factors in regulation of signaling in breast cancer. These findings add to the growing understanding of how the oncoprotein MUC1 alters breast cancer signaling, specifically in relationship to the APC tumor suppressor.