title: STAT3 activation in HER2-overexpressing breast cancer promotes epithelial-mesenchymal transition and cancer stem cell traits.
abstract: Clinically, HER2 proto-oncogene amplification is found in about 25-30% of human breast cancers, where it is correlated to a poor prognosis. Constitutive STAT3 activation is found in about 50-60% of the breast tumors and associated with tumorigenesis and drug resistance. In this study, we showed that STAT3 was phosphorylated in HER2-overexpressing, ER-positive human breast tumors and, furthermore, phosphorylated STAT3 promoted the stem-like cell phenotype. We examined the dysregulation of the stem cell markers (Oct-4, Sox-2 and CD44) and the tumorsphere formation in HER2-overexpressing human breast cancer cell lines. We demonstrated that the STAT3 inhibitor, Stattic, treatment abolished the cancer stem cell phenotype in HER2-positive breast cancers. Combined treatment of Herceptin and Stattic showed the synergistic effect on the cancer cell growth in vitro. In addition, when the STAT3 gene was knocked down, the expression of the stem cell markers Oct-4, Sox-2 and CD44 were downregulated and tumorsphere formation was abolished. HER2-elicited STAT3 signaling may provide a potential model for drug resistance induced by stem-like cell characteristics. This mechanism may be responsible for acquiring resistance to Herceptin in the treatment of HER2-overexpressing breast tumors. Based on our findings, targeting pSTAT3 could overcome Herceptin-induced resistance in HER2-overexpressing breast tumors.
authors.affiliation: Division of Cancer Research and Training, Charles R. Drew University of Medicine and Science, Los Angeles, CA, USA.
authors.forename: Seyung S
authors.initials: SS
authors.lastname: Chung
authors.affiliation: Division of Cancer Research and Training, Charles R. Drew University of Medicine and Science, Los Angeles, CA, USA.
authors.forename: Nolan
authors.initials: N
authors.lastname: Giehl
authors.affiliation: Division of Cancer Research and Training, Charles R. Drew University of Medicine and Science, Los Angeles, CA, USA.
authors.forename: Yanyuan
authors.initials: Y
authors.lastname: Wu
authors.affiliation: Division of Cancer Research and Training, Charles R. Drew University of Medicine and Science, Los Angeles, CA, USA.
authors.forename: Jaydutt V
authors.initials: JV
authors.lastname: Vadgama
mesh_terms: D000818:Animals; D061067:Antibodies, Monoclonal, Humanized / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000494:pharmacology; D000971:Antineoplastic Combined Chemotherapy Protocols; D014408:Biomarkers, Tumor; D015153:Blotting, Western; D001943:Breast Neoplasms / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology*; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D003499:Cyclic S-Oxides / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm; D004357:Drug Synergism; D058750:Epithelial-Mesenchymal Transition; D005260:Female; D006801:Humans; D047468:Immunoprecipitation; D051379:Mice; D041681:NIH 3T3 Cells; D014411:Neoplastic Stem Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D010766:Phosphorylation / Q000187:drug effects; D000090063:Proto-Oncogene Mas; D012333:RNA, Messenger / Q000235:genetics; D034741:RNA, Small Interfering / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D050796:STAT3 Transcription Factor / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D046888:Tissue Array Analysis; D000068878:Trastuzumab; D014407:Tumor Cells, Cultured
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; D003499:Cyclic S-Oxides; D000090063:Proto-Oncogene Mas; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D018719:Erb-b2 Receptor Tyrosine Kinases; D050796:STAT3 Transcription Factor; D000068878:Trastuzumab; C000715470:MAS1 protein, human; C494086:STAT3 protein, human; C517409:stattic; C508053:ERBB2 protein, human