title: 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.affiliation: Genus Oncology, Boston, MA, USA.
authors.forename: D
authors.initials: D
authors.lastname: Raina
authors.affiliation: Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.
authors.forename: Y
authors.initials: Y
authors.lastname: Uchida
authors.affiliation: Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.
authors.forename: A
authors.initials: A
authors.lastname: Kharbanda
authors.affiliation: Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.
authors.forename: H
authors.initials: H
authors.lastname: Rajabi
authors.affiliation: Genus Oncology, Boston, MA, USA.
authors.forename: G
authors.initials: G
authors.lastname: Panchamoorthy
authors.affiliation: Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.
authors.forename: C
authors.initials: C
authors.lastname: Jin
authors.affiliation: Genus Oncology, Boston, MA, USA.
authors.forename: S
authors.initials: S
authors.lastname: Kharbanda
authors.affiliation: Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
authors.forename: M
authors.initials: M
authors.lastname: Scaltriti
authors.affiliation: Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
authors.forename: J
authors.initials: J
authors.lastname: Baselga
authors.affiliation: Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.
authors.forename: D
authors.initials: D
authors.lastname: Kufe
mesh_terms: D000818:Animals; D061067:Antibodies, Monoclonal, Humanized / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000494:pharmacology; D001943:Breast Neoplasms / Q000188:drug therapy / Q000235:genetics*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D019927:Cyclin E / Q000096:biosynthesis; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000096:biosynthesis; D015536:Down-Regulation; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D000077341:Lapatinib; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D018396:Mucin-1 / Q000096:biosynthesis / Q000235:genetics* / Q000378:metabolism; D010455:Peptides / Q000494:pharmacology; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000096:biosynthesis; D011799:Quinazolines / Q000494:pharmacology; D034622:RNA Interference; D034741:RNA, Small Interfering; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000096:biosynthesis / Q000378:metabolism*; D000068878:Trastuzumab; D023041:Xenograft Model Antitumor Assays
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D019927:Cyclin E; D050760:Cyclin-Dependent Kinase Inhibitor p27; D000077341:Lapatinib; D018396:Mucin-1; D010455:Peptides; D051057:Proto-Oncogene Proteins c-akt; D011799:Quinazolines; D034741:RNA, Small Interfering; D018719:Erb-b2 Receptor Tyrosine Kinases; D000068878:Trastuzumab; C582521:(arginine)9-cysteinyl-glutaminyl-cysteinyl-arginyl-arginyl-lysyl-asparagine; C060192:MUC1 protein, human; C508053:ERBB2 protein, human
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