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Rich66 · 05-06-2009, 05:04 PM

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 bindsβ-catenin while simultaneously inhibiting the degradationof the epidermal growth factor receptor (EGFR), resulting inenhanced transformation and metastasis. The purpose of thisstudy was to design a peptide-based therapy that would blockthese intracellular protein-protein interactions as a treatmentfor metastatic breast cancer.
Experimental Design: The amino acid residues responsible forthese interactions lie in tandem in the cytoplasmic domain ofMUC1, and we have targeted this sequence to produce a MUC1 peptidethat blocks the protumorigenic functions of MUC1. We designedthe MUC1 inhibitory peptide (MIP) to block the intracellularinteractions between MUC1/β-catenin and MUC1/EGFR. To allowfor cellular uptake we synthesized MIP adjacent to the proteintransduction domain, PTD4 (PMIP).
Results: We have found that PMIP acts in a dominant-negativefashion, blocking both MUC1/β-catenin and MUC1/EGFR interactions.In addition, PMIP induces ligand-dependent reduction of EGFRlevels. These effects correspond to a significant reductionin proliferation, migration, and invasion of metastatic breastcancer cells in vitro, and inhibition of tumor growth and recurrencein an established MDA-MB-231 immunocompromised (SCID) mousemodel. Importantly, PMIP also inhibits genetically driven breastcancer progression, as injection of tumor-bearing MMTV-pyV mTtransgenic mice with PMIP results in tumor regression and asignificant inhibition of tumor growth rate.
Conclusions: These data show that intracellular MUC1 peptidespossess significant antitumor activity and have important clinicalapplications in the treatment of cancer.

05-06-2009, 05:04 PM	#2
Rich66 Senior Member Join Date: Feb 2008 Location: South East Wisconsin Posts: 3,431	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 bindsβ-catenin while simultaneously inhibiting the degradationof the epidermal growth factor receptor (EGFR), resulting inenhanced transformation and metastasis. The purpose of thisstudy was to design a peptide-based therapy that would blockthese intracellular protein-protein interactions as a treatmentfor metastatic breast cancer. Experimental Design: The amino acid residues responsible forthese interactions lie in tandem in the cytoplasmic domain ofMUC1, and we have targeted this sequence to produce a MUC1 peptidethat blocks the protumorigenic functions of MUC1. We designedthe MUC1 inhibitory peptide (MIP) to block the intracellularinteractions between MUC1/β-catenin and MUC1/EGFR. To allowfor cellular uptake we synthesized MIP adjacent to the proteintransduction domain, PTD4 (PMIP). Results: We have found that PMIP acts in a dominant-negativefashion, blocking both MUC1/β-catenin and MUC1/EGFR interactions.In addition, PMIP induces ligand-dependent reduction of EGFRlevels. These effects correspond to a significant reductionin proliferation, migration, and invasion of metastatic breastcancer cells in vitro, and inhibition of tumor growth and recurrencein an established MDA-MB-231 immunocompromised (SCID) mousemodel. Importantly, PMIP also inhibits genetically driven breastcancer progression, as injection of tumor-bearing MMTV-pyV mTtransgenic mice with PMIP results in tumor regression and asignificant inhibition of tumor growth rate. Conclusions: These data show that intracellular MUC1 peptidespossess significant antitumor activity and have important clinicalapplications in the treatment of cancer.