Intracellular MUC1 peptides inhibit cancer progression

Benjamin G. Bitter, Ina Menzl, Carmen L. Huerta, Barbara Sands, Wendy Knowlton, Andrew Chang, Joyce A. Schroeder

Research output: Contribution to journalArticle

57 Scopus citations

Abstract

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 peptidebased 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 MUCI/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 MUCl/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.

Original languageEnglish (US)
Pages (from-to)100-109
Number of pages10
JournalClinical Cancer Research
Volume15
Issue number1
DOIs
StatePublished - Jan 1 2009

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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    Bitter, B. G., Menzl, I., Huerta, C. L., Sands, B., Knowlton, W., Chang, A., & Schroeder, J. A. (2009). Intracellular MUC1 peptides inhibit cancer progression. Clinical Cancer Research, 15(1), 100-109. https://doi.org/10.1158/1078-0432.CCR-08-1745