Intracellular MUC1 peptides inhibit cancer progression

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

Research output: Contribution to journalArticle

54 Citations (Scopus)

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

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Epidermal Growth Factor Receptor
Catenins
Peptides
Neoplasms
Breast Neoplasms
SCID Mice
Oncogene Proteins
Growth
Transgenic Mice
Proteins
Research Design
Therapeutics
Neoplasm Metastasis
Ligands
Amino Acids
Recurrence
Injections

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

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

Intracellular MUC1 peptides inhibit cancer progression. / Bitter, Benjamin G.; Menzl, Ina; Huerta, Carmen L.; Sands, Barbara; Knowlton, Wendy; Chang, Andrew; Schroeder, Joyce.

In: Clinical Cancer Research, Vol. 15, No. 1, 01.01.2009, p. 100-109.

Research output: Contribution to journalArticle

Bitter, BG, Menzl, I, Huerta, CL, Sands, B, Knowlton, W, Chang, A & Schroeder, J 2009, 'Intracellular MUC1 peptides inhibit cancer progression', Clinical Cancer Research, vol. 15, no. 1, pp. 100-109. https://doi.org/10.1158/1078-0432.CCR-08-1745
Bitter BG, Menzl I, Huerta CL, Sands B, Knowlton W, Chang A et al. Intracellular MUC1 peptides inhibit cancer progression. Clinical Cancer Research. 2009 Jan 1;15(1):100-109. https://doi.org/10.1158/1078-0432.CCR-08-1745
Bitter, Benjamin G. ; Menzl, Ina ; Huerta, Carmen L. ; Sands, Barbara ; Knowlton, Wendy ; Chang, Andrew ; Schroeder, Joyce. / Intracellular MUC1 peptides inhibit cancer progression. In: Clinical Cancer Research. 2009 ; Vol. 15, No. 1. pp. 100-109.
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