title: Association of Wwox with ErbB4 in breast cancer.
abstract: WWOX, WW domain-containing oxidoreductase, is a tumor suppressor that is altered in many human cancers, including breast cancer. Wwox interacts with the ErbB4 receptor, reduces nuclear translocation of the cleaved intracellular domain of ErbB4, and inhibits its transactivation function mediated through Yes-associated protein. Here, we assessed the clinical significance of the Wwox-ErbB4 association. We determined Wwox protein expression by immunohistochemistry in a series of 556 breast cancers. Wwox expression was absent in 36% of the cancers, and loss of Wwox expression was associated with unfavorable outcome (P = 0.02). Membranous location of ErbB4 was associated with favorable survival compared with women whose cancer lacked such ErbB4 expression (P = 0.02). Wwox expression was strongly associated with membranous ErbB4 localization (P = 0.0003) and with overall ErbB4 expression (P = 0.0002). Coexpression of membranous ErbB4 and Wwox was associated with favorable outcome compared with cases with membranous ErbB4 and no Wwox immunoreactivity (P = 0.002). In vitro, Wwox associated with the two ErbB4 isoforms, JM-a CYT-1 and JM-a CYT-2, expressed in breast cancer. Moreover, expression of Wwox both in vitro and in vivo led to accumulation of total full-length membrane-associated ErbB4. These results suggest that expression of Wwox is associated with ErbB4 expression and that their coexpression has prognostic significance in breast cancer.
authors.affiliation: Department of Molecular Virology, Immunology and Medical Genetics, Human Cancer Genetics Program, Comprehensive Cancer Center, Ohio State University, Columbus, Ohio 43210, USA. rami.aqeilan@osumc.edu
authors.forename: Rami I
authors.initials: RI
authors.lastname: Aqeilan
authors.forename: Valentina
authors.initials: V
authors.lastname: Donati
authors.forename: Eugenio
authors.initials: E
authors.lastname: Gaudio
authors.forename: Milena S
authors.initials: MS
authors.lastname: Nicoloso
authors.forename: Maria
authors.initials: M
authors.lastname: Sundvall
authors.forename: Anna
authors.initials: A
authors.lastname: Korhonen
authors.forename: Johan
authors.initials: J
authors.lastname: Lundin
authors.forename: Jorma
authors.initials: J
authors.lastname: Isola
authors.forename: Marius
authors.initials: M
authors.lastname: Sudol
authors.forename: Heikki
authors.initials: H
authors.lastname: Joensuu
authors.forename: Carlo M
authors.initials: CM
authors.lastname: Croce
authors.forename: Klaus
authors.initials: K
authors.lastname: Elenius
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D019556:COS Cells; D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000378:metabolism; D002467:Cell Nucleus / Q000378:metabolism; D002522:Chlorocebus aethiops; D066246:ErbB Receptors / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008207:Lymphatic Metastasis; D010088:Oxidoreductases / Q000096:biosynthesis / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D020033:Protein Isoforms; D066247:Receptor, ErbB-4; D014162:Transfection; D025521:Tumor Suppressor Proteins / Q000096:biosynthesis / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D015854:Up-Regulation; D000074584:WW Domain-Containing Oxidoreductase
chemical_list: D020033:Protein Isoforms; D025521:Tumor Suppressor Proteins; D010088:Oxidoreductases; D000074584:WW Domain-Containing Oxidoreductase; C486071:WWOX protein, human; C587689:ERBB4 protein, human; D066246:ErbB Receptors; D066247:Receptor, ErbB-4