Cyclooxygenase-2 is a target gene of rho GDP dissociation inhibitor beta in breast cancer cells.
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.
Schunke
Dario
D
Klinik für Gynäkologie, Universität Halle, Halle (Saale), Germany.
Span
Paul
P
Ronneburg
Henrike
H
Dittmer
Angela
A
Vetter
Martina
M
Holzhausen
Hans-Jürgen
HJ
Kantelhardt
Eva
E
Krenkel
Sylke
S
Müller
Volkmar
V
Sweep
Fred C G J
FC
Thomssen
Christoph
C
Dittmer
Jürgen
J
D001706:Biopsy; D001943:Breast Neoplasms / Q000201:enzymology / Q000378:metabolism* / Q000401:mortality; D002460:Cell Line; D045744:Cell Line, Tumor; D002465:Cell Movement; D051546:Cyclooxygenase 2 / Q000096:biosynthesis / Q000502:physiology*; D018450:Disease Progression; D015971:Gene Expression Regulation, Enzymologic; D015972:Gene Expression Regulation, Neoplastic; D020730:Guanine Nucleotide Dissociation Inhibitors / Q000378:metabolism*; D006801:Humans; D020411:Oligonucleotide Array Sequence Analysis; D011379:Prognosis; D050784:Proto-Oncogene Protein c-ets-1 / Q000096:biosynthesis; D016896:Treatment Outcome; D025521:Tumor Suppressor Proteins / Q000378:metabolism*; D062947:rho-Specific Guanine Nucleotide Dissociation Inhibitors
C494041:ETS1 protein, human; D020730:Guanine Nucleotide Dissociation Inhibitors; D050784:Proto-Oncogene Protein c-ets-1; D025521:Tumor Suppressor Proteins; D062947:rho-Specific Guanine Nucleotide Dissociation Inhibitors; D051546:Cyclooxygenase 2