Targeting the MUC1-C oncoprotein downregulates HER2 activation and abrogates trastuzumab resistance in breast cancer cells.

Abstract

Patients with HER2-positive breast cancer often exhibit intrinsic or acquired resistance to trastuzumab treatment. The transmembrane mucin 1 (MUC1) oncoprotein is aberrantly overexpressed in breast cancer cells and associates with HER2. The present studies demonstrate that silencing MUC1 C-terminal subunit (MUC1-C) in HER2-overexpressing SKBR3 and BT474 breast cancer cells results in the downregulation of constitutive HER2 activation. Moreover, treatment with the MUC1-C inhibitor, GO-203, was associated with disruption of MUC1-C/HER2 complexes and decreases in tyrosine-phosphorylated HER2 (p-HER2) levels. In studies of trastuzumab-resistant SKBR3R and BT474R cells, we found that the association between MUC1-C and HER2 is markedly increased (∼20-fold) as compared with that in sensitive cells. In addition, silencing MUC1-C in the trastuzumab-resistant cells or treatment with GO-203 decreased p-HER2 and AKT activation. Moreover, targeting MUC1-C was associated with the downregulation of phospho-p27 and cyclin E, which confer trastuzumab resistance. Consistent with these results, targeting MUC1-C inhibited the growth and clonogenic survival of both trastuzumab-resistant cells. Our results further demonstrate that silencing MUC1-C reverses resistance to trastuzumab and that the combination of GO-203 and trastuzumab is highly synergistic. These findings indicate that MUC1-C contributes to constitutive activation of the HER2 pathway and that targeting MUC1-C represents a potential approach to abrogate trastuzumab resistance.

• Authors: D Raina, Y Uchida, A Kharbanda, H Rajabi, G Panchamoorthy, C Jin, S Kharbanda, M Scaltriti, J Baselga, D Kufe
• Journal: Oncogene (Oncogene) Vol. 33 Issue 26 Pg. 3422-31 (Jun 26 2014) ISSN: 1476-5594 [Electronic] England
• PMID: 23912457 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• (arginine)9-cysteinyl-glutaminyl-cysteinyl-arginyl-arginyl-lysyl-asparagine
• Antibodies, Monoclonal, Humanized
• Antineoplastic Agents
• Cyclin E
• MUC1 protein, human
• Mucin-1
• Peptides
• Quinazolines
• RNA, Small Interfering
• Lapatinib
• Cyclin-Dependent Kinase Inhibitor p27
• ERBB2 protein, human
• Receptor, ErbB-2
• Proto-Oncogene Proteins c-akt
• Trastuzumab

Topics

• Animals
• Antibodies, Monoclonal, Humanized (pharmacology)
• Antineoplastic Agents (pharmacology)
• Breast Neoplasms (drug therapy, genetics)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Cyclin E (biosynthesis)
• Cyclin-Dependent Kinase Inhibitor p27 (biosynthesis)
• Down-Regulation
• Drug Resistance, Neoplasm (genetics)
• Female
• Gene Expression Regulation, Neoplastic
• Humans
• Lapatinib
• Mice
• Mice, Inbred BALB C
• Mice, Nude
• Mucin-1 (biosynthesis, genetics, metabolism)
• Peptides (pharmacology)
• Phosphorylation
• Proto-Oncogene Proteins c-akt (biosynthesis)
• Quinazolines (pharmacology)
• RNA Interference
• RNA, Small Interfering
• Receptor, ErbB-2 (biosynthesis, metabolism)
• Trastuzumab
• Xenograft Model Antitumor Assays