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Signaling and Regulation

Heregulin Targets -Catenin to the Nucleolus by a Mechanism Dependent on the DF3/MUC1 Oncoprotein¹

¹ Dana-Farber Cancer Institute, Harvard Medical School and ² ILEX Products, Inc., Boston, MA

Requests for reprints: Donald Kufe, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115. Phone: (617) 632-3141; Fax: (617) 632-2934. E-mail: donald_kufe{at}dfci.harvard.edu

The DF3/MUC1 transmembrane oncoprotein is aberrantly overexpressed in most human breast carcinomas and interacts with the Wnt effector -catenin. Here, we demonstrate that MUC1 associates constitutively with ErbB2 in human breast cancer cells and that treatment with heregulin/neuregulin-1 (HRG) increases the formation of MUC1-ErbB2 complexes. The importance of the MUC1-ErbB2 interaction is supported by the demonstration that HRG induces binding of MUC1 and -catenin and targeting of the MUC1--catenin complex to the nucleolus. Significantly, nucleolar localization of -catenin in response to HRG is dependent on MUC1 expression. Moreover, mutation of a RRK motif in the MUC1 cytoplasmic domain abrogates HRG-induced nucleolar localization of MUC1 and -catenin. In concert with these results, we show nucleolar localization of MUC1 and -catenin in human breast carcinomas but not in normal mammary ductal epithelium. These findings demonstrate that MUC1 functions in cross talk between ErbB2 and Wnt pathways by acting as a shuttle for HRG-induced nucleolar targeting of -catenin.

Key Words: MUC1 • ErbB2 • heregulin • -catenin • nucleolus • breast cancer

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