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

Abstract

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

Characterization of EHop-016, Novel Small Molecule Inhibitor of Rac GTPase

“…Although a single report demonstrated increased migration of MDA-MB-435 and MDA-MB-231 metastatic breast cancer cells following 50 -100 M NSC23766, in our hands, treatment with 100 M NSC23766 for 24 h resulted in a 75% decrease in MDA-MB-435 cell migration (data not shown). Moreover, there are several reports of decreased cell migration in metastatic breast cancer cells following direct inhibition of Rac1 and Rac3 by expression of dominant negative Rac and siRNA knockdown of Rac expression or by indirect inhibition of Rac by blocking upstream effector activity (13,18,57,(82)(83)(84)(85)(86)(87).…”

RhoGDI2 Expression Is Associated with Tumor Growth and Malignant Progression of Gastric Cancer

“…This suggests that these two Rho GTPase regulators seem to function cooperatively as signal transducers in the T-cell receptor signaling pathway. Recently, Schunke et al also showed that RhoGDI2 cooperates with Vav1 for NFAT activation in breast cancer cells (33).…”

“…The expression of h1-integrin has been known to be regulated by RhoGDI2 in breast cancer cells (18). Cyclooxygenase-2, a major regulator of invasion and metastasis in breast cancer cells (34 -36), has also been identified as a target gene of RhoGDI2 (33). We attempted to verify whether the expression of h1-integrin or cyclooxygenase-2 is regulated by RhoGDI2 in gastric cancer cells, but failed to see any difference in the expression of these proteins in RhoGDI2-expressing or RhoGDI2-depleting gastric cancer cells compared with control cells (data not shown).…”

Clinical Omics Analysis of Colorectal Cancer Incorporating Copy Number Aberrations and Gene Expression Data

“…ARHGDIB, working with vav 1 guanine nucleotide exchange factor (VAV1), activates the nuclear factor of activated T-cells 1 (NFAT1) and results in transcription regulation of the tumor-related gene cyclooxygenase (COX2). COX2 is related to cancer progression, and Schunke reported that the activation of COX2 in breast cancer lowers the survival rate, and promotes metastasis to lung or bone 39. On the other hand, ARHGDIB also has an ability to inhibit Rho GTPase, which inhibits cancer invasion.…”