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Association of Wwox with ErbB4 in Breast Cancer

¹ Department of Molecular Virology, Immunology and Medical Genetics, Human Cancer Genetics Program, Comprehensive Cancer Center, Ohio State University, Columbus, Ohio; ² MediCity Research Laboratory, and Department of Medical Biochemistry and Molecular Biology, University of Turku; ³ Turku Postgraduate School of Biomedical Sciences; ⁴ Department of Oncology, Turku University Central Hospital, Turku, Finland; ⁵ Department of Oncology, University of Helsinki, Helsinki, Finland; ⁶ Laboratory of Cancer Biology, Institute of Medical Technology, Tampere University, and Tampere University Hospital, Tampere, Finland; and ⁷ Weis Center for Research, Geisinger Clinic, Danville, Pennsylvania

Requests for reprints: Rami I. Aqeilan, Human Cancer Genetics, Ohio State University, Biomedical Research Tower, Room 1088, 460 West 12th Avenue, Columbus, OH 43210. Phone: 614-292-5906; Fax: 614-292-4097; E-mail: rami.aqeilan{at}osumc.edu or Klaus Elenius, Department of Medical Biochemistry and Molecular Biology, University of Turku, Kiinamyllynkatu 10, FIN-20520 Turku, Finland. Phone: 358-2-3337569; Fax: 358-2-3337229; E-mail: klaus.elenius{at}utu.fi.

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. [Cancer Res 2007;67(19):9330–6]

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