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Cyclooxygenase-2 Is a Target Gene of Rho GDP Dissociation Inhibitor ß in Breast Cancer Cells

¹ Klinik für Gynäkologie and ² Institut für Pathologie, Universität Halle, Halle (Saale), Germany; ³ Department of Chemical Endocrinology, Radboud University Nijmegen Medical Centre, Nijmegen, the Netherlands; and ⁴ Klinik für Gynäkologie, Universitätsklinikum Hamburg-Eppendorf, Hamburg, Germany

Requests for reprints: Jürgen Dittmer, Klinik für Gynäkologie, Universität Halle, Ernst-Grube-Str. 40, 06097 Halle (Saale), Germany. Phone: 49-345-557-1338; Fax: 49-345-557-5261; E-mail: juergen.dittmer{at}medizin.uni-halle.de.

Rho GDP dissociation inhibitor ß (Rho-GDIß), an inhibitor of Rho GTPases, is primarily expressed by hematopoietic cells but is also found in epithelial cancer cells. Recently, we have identified Rho-GDIß as a target of the transcription factor Ets1. Here, we show that, in breast cancer cells, Ets1 regulates Rho-GDIß expression and binds to the upstream region of the Rho-GDIß gene. Furthermore, in primary breast cancer, Rho-GDIß is coexpressed with Ets1. Studying the function of Rho-GDIß in breast cancer, we found that a Rho-GDIß–specific small interfering RNA increased cellular migration but also decreased the expression of cyclooxygenase-2 (Cox-2) oncogene as shown by microarray, quantitative reverse transcription-PCR, and Western blot analyses. Further studies revealed that Rho-GDIß regulates Cox-2 gene at least partly on the transcriptional level, most likely by activating nuclear factor of activated T cells 1 (NFAT-1). Vav-1, an interaction partner of Rho-GDIß, was also found to interfere with Cox-2 expression and NFAT-1 cellular distribution, suggesting a cooperative action of Rho-GDIß and Vav-1 on Cox-2 expression. To explore the importance of Rho-GDIß for the survival of breast cancer patients, two cohorts, including 263 and 117 patients, were analyzed for clinical outcome in relation to Rho-GDIß RNA and protein levels, respectively. Expression of Rho-GDIß was not associated with either disease-free or overall survival in the two patient population. Our data suggest that the expression of Rho-GDIß in breast cancer is neither beneficial nor disadvantageous to the patient. This may be the net effect of two opposing activities of Rho-GDIß, one that suppresses tumor progression by inhibiting migration and the other that stimulates it by enhancing Cox-2 expression. [Cancer Res 2007;67(22):10694–702]

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