Intracellular MUC1 peptides inhibit cancer progression.
OBJECTIVE
During cancer progression, the oncoprotein MUC1 binds beta-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.


METHODS
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/beta-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/beta-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.
Bitler
Benjamin G
BG
Arizona Cancer Center, University of Arizona, Tucson, Arizona, USA.
Menzl
Ina
I
Huerta
Carmen L
CL
Sands
Barbara
B
Knowlton
Wendy
W
Chang
Andrew
A
Schroeder
Joyce A
JA
D000595:Amino Acid Sequence; D000818:Animals; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D003593:Cytoplasm / Q000378:metabolism; D018450:Disease Progression; D066246:ErbB Receptors / Q000378:metabolism; D006801:Humans; D008325:Mammary Neoplasms, Experimental / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D051379:Mice; D016513:Mice, SCID; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D018396:Mucin-1 / Q000737:chemistry / Q000502:physiology*; D009368:Neoplasm Transplantation; D010455:Peptides / Q000737:chemistry / Q000494:pharmacology*; D017434:Protein Structure, Tertiary; D051176:beta Catenin / Q000378:metabolism
D018396:Mucin-1; C570660:PMIP peptide; D010455:Peptides; D051176:beta Catenin; D066246:ErbB Receptors