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Cyclooxygenase-2 is a target gene of rho GDP dissociation inhibitor beta in breast cancer cells.

Schunke D, Span P, Ronneburg H, Dittmer A, Vetter M, Holzhausen HJ, Kantelhardt E, Krenkel S, Müller V, Sweep FC, Thomssen C, Dittmer J

Klinik für Gynäkologie, Universität Halle, Halle (Saale), Germany.

Rho GDP dissociation inhibitor beta (Rho-GDI beta), an inhibitor of Rho GTPases, is primarily expressed by hematopoietic cells but is also found in epithelial cancer cells. Recently, we have identified Rho-GDI beta as a target of the transcription factor Ets1. Here, we show that, in breast cancer cells, Ets1 regulates Rho-GDI beta expression and binds to the upstream region of the Rho-GDI beta gene. Furthermore, in primary breast cancer, Rho-GDI beta is coexpressed with Ets1. Studying the function of Rho-GDI beta in breast cancer, we found that a Rho-GD beta-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-GDI beta 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-GDI beta, was also found to interfere with Cox-2 expression and NFAT-1 cellular distribution, suggesting a cooperative action of Rho-GDI beta and Vav-1 on Cox-2 expression. To explore the importance of Rho-GDI beta for the survival of breast cancer patients, two cohorts, including 263 and 117 patients, were analyzed for clinical outcome in relation to Rho-GDI beta RNA and protein levels, respectively. Expression of Rho-GDI beta was not associated with either disease-free or overall survival in the two patient population. Our data suggest that the expression of Rho-GDI beta in breast cancer is neither beneficial nor disadvantageous to the patient. This may be the net effect of two opposing activities of Rho-GDI beta, one that suppresses tumor progression by inhibiting migration and the other that stimulates it by enhancing Cox-2 expression.

Published 16 November 2007 in Cancer Res, 67(22): 10694-702.
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