Clinical Cancer Research 15, 100, January 1, 2009. doi: 10.1158/1078-0432.CCR-08-1745
© 2009 American Association for Cancer Research
Cancer Therapy: Preclinical
Intracellular MUC1 Peptides Inhibit Cancer Progression
Benjamin G. Bitler2, Ina Menzl2, Carmen L. Huerta1, Barbara Sands1, Wendy Knowlton1, Andrew Chang1 and Joyce A. Schroeder1,2,3 Authors' Affiliations: 1 Department of Molecular and Cellular Biology, 2 Arizona Cancer Center, and 3 Bio5 Institute, University of Arizona, Tucson, Arizona
Requests for reprints: Joyce A. Schroeder, Molecular and Cellular Biology, Arizona Cancer Center, PO Box 245024, Tucson, AZ 85724-5024. Phone: 520-626-1384; Fax: 520-626-3764; E-mail: jschroeder@azcc.arizona.edu.
Purpose: During cancer progression, the oncoprotein MUC1 binds
β-catenin while simultaneously inhibiting the degradation
of the epidermal growth factor receptor (EGFR), resulting in
enhanced transformation and metastasis. The purpose of this
study was to design a peptide-based therapy that would block
these intracellular protein-protein interactions as a treatment
for metastatic breast cancer.
Experimental Design: The amino acid residues responsible for
these interactions lie in tandem in the cytoplasmic domain of
MUC1, and we have targeted this sequence to produce a MUC1 peptide
that blocks the protumorigenic functions of MUC1. We designed
the MUC1 inhibitory peptide (MIP) to block the intracellular
interactions between MUC1/β-catenin and MUC1/EGFR. To allow
for cellular uptake we synthesized MIP adjacent to the protein
transduction domain, PTD4 (PMIP).
Results: We have found that PMIP acts in a dominant-negative
fashion, blocking both MUC1/β-catenin and MUC1/EGFR interactions.
In addition, PMIP induces ligand-dependent reduction of EGFR
levels. These effects correspond to a significant reduction
in proliferation, migration, and invasion of metastatic breast
cancer cells
in vitro, and inhibition of tumor growth and recurrence
in an established MDA-MB-231 immunocompromised (SCID) mouse
model. Importantly, PMIP also inhibits genetically driven breast
cancer progression, as injection of tumor-bearing MMTV-pyV mT
transgenic mice with PMIP results in tumor regression and a
significant inhibition of tumor growth rate.
Conclusions: These data show that intracellular MUC1 peptides
possess significant antitumor activity and have important clinical
applications in the treatment of cancer.