title: Prominent Oncogenic Roles of EVI1 in Breast Carcinoma.
abstract: Overexpression of the EVI1 oncogene is associated typically with aggressive myeloid leukemia, but is also detectable in breast carcinoma where its contributions are unexplored. Analyzing a tissue microarray of 608 breast carcinoma patient specimens, we documented EVI1 overexpression in both estrogen receptor-positive (ER+) and estrogen receptor-negative (ER-) breast carcinomas. Here, we report prognostic relevance of EVI1 overexpression in triple-negative breast carcinoma but not in the HER2-positive breast carcinoma subset. In human breast cancer cells, EVI1 silencing reduced proliferation, apoptosis resistance, and tumorigenicity, effects rescued by estrogen supplementation in ER+breast carcinoma cells. Estrogen addition restored ERK phosphorylation in EVI1-silenced cells, suggesting that EVI1 and estradiol signaling merge in MAPK activation. Conversely, EVI1 silencing had no effect on constitutive ERK activity in HER2+breast carcinoma cells. Microarray analyses revealed G-protein-coupled receptor (GPR) signaling as a prominent EVI1 effector mechanism in breast carcinoma. Among others, the GPR54-ligand KISS1 was identified as a direct transcriptional target of EVI1, which together with other EVI1-dependent cell motility factors such as RHOJ regulated breast carcinoma cell migration. Overall, our results establish the oncogenic contributions of EVI1 in ER- and HER2-negative subsets of breast cancer.Cancer Res; 77(8); 2148-60. ©2017 AACR.
authors.affiliation: Department of Biomedicine, University of Basel and University Hospital Basel, Basel, Switzerland.|Department of Hematology, Oncology, Rheumatology, Immunology and Pulmonology, University of Tuebingen, Tuebingen, Germany.
authors.forename: Hui
authors.initials: H
authors.lastname: Wang
authors.affiliation: Department of Biomedicine, University of Basel and University Hospital Basel, Basel, Switzerland.
authors.forename: Thorsten
authors.initials: T
authors.lastname: Schaefer
authors.affiliation: Department of Biomedicine, University of Basel and University Hospital Basel, Basel, Switzerland.
authors.forename: Martina
authors.initials: M
authors.lastname: Konantz
authors.affiliation: Department of Prostate Cancer Research, Institute of Pathology, University Hospital of Bonn, Bonn, Germany.
authors.forename: Martin
authors.initials: M
authors.lastname: Braun
authors.affiliation: Pathology and Molecular Pathology, University Hospital Zurich, Zurich, Switzerland.
authors.forename: Zsuzsanna
authors.initials: Z
authors.lastname: Varga
authors.affiliation: Department of Biomedicine, University of Basel and University Hospital Basel, Basel, Switzerland.
authors.forename: Anna M
authors.initials: AM
authors.lastname: Paczulla
authors.affiliation: Department of Hematology, Oncology, Rheumatology, Immunology and Pulmonology, University of Tuebingen, Tuebingen, Germany.
authors.forename: Selina
authors.initials: S
authors.lastname: Reich
authors.affiliation: Department of Biomedicine, University of Basel and University Hospital Basel, Basel, Switzerland.
authors.forename: Francis
authors.initials: F
authors.lastname: Jacob
authors.affiliation: Institute of Pathology, Campus Luebeck and Research Center Borstel, Leibniz Center for Medicine and Biosciences, Luebeck and Borstel, Germany.
authors.forename: Sven
authors.initials: S
authors.lastname: Perner
authors.affiliation: Pathology and Molecular Pathology, University Hospital Zurich, Zurich, Switzerland.
authors.forename: Holger
authors.initials: H
authors.lastname: Moch
authors.affiliation: Department of Gynecology and Obstetrics, University Hospital Duesseldorf, Duesseldorf, Germany.|Women's Hospital, University Hospital Tuebingen, Tuebingen, Germany.
authors.forename: Tanja N
authors.initials: TN
authors.lastname: Fehm
authors.affiliation: Department of Hematology, Oncology, Rheumatology, Immunology and Pulmonology, University of Tuebingen, Tuebingen, Germany.
authors.forename: Lothar
authors.initials: L
authors.lastname: Kanz
authors.affiliation: Interfaculty Institute for Biochemistry, University of Tuebingen, Tuebingen, Germany.|German Cancer Consortium (DKTK) and German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: Klaus
authors.initials: K
authors.lastname: Schulze-Osthoff
authors.affiliation: Department of Biomedicine, University of Basel and University Hospital Basel, Basel, Switzerland. claudia.lengerke@unibas.ch.|Department of Hematology, Oncology, Rheumatology, Immunology and Pulmonology, University of Tuebingen, Tuebingen, Germany.|Clinic for Hematology, University of Basel and University Hospital Basel, Basel, Switzerland.
authors.forename: Claudia
authors.initials: C
authors.lastname: Lengerke
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000235:genetics; D001943:Breast Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000235:genetics; D004268:DNA-Binding Proteins / Q000096:biosynthesis / Q000235:genetics*; D005260:Female; D055785:Gene Knockdown Techniques; D064593:Heterografts; D006801:Humans; D007150:Immunohistochemistry; D000074008:MDS1 and EVI1 Complex Locus Protein; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D011519:Proto-Oncogenes / Q000235:genetics*; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism; D011960:Receptors, Estrogen / Q000378:metabolism; D014157:Transcription Factors / Q000096:biosynthesis / Q000235:genetics*; D064726:Triple Negative Breast Neoplasms / Q000235:genetics / Q000378:metabolism; D015027:Zebrafish
chemical_list: D004268:DNA-Binding Proteins; D000074008:MDS1 and EVI1 Complex Locus Protein; D018719:Erb-b2 Receptor Tyrosine Kinases; D011960:Receptors, Estrogen; D014157:Transcription Factors; C063575:MECOM protein, human; C508053:ERBB2 protein, human