No 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]

<div>Abstract<p>Rho GDP dissociation inhibitor β (Rho-GDIβ), an inhibitor of Rho GTPases, is primarily expressed by hematopoietic cells but is also found in epithelial cancer cells. Recently, we have identified Rho-GDIβ as a target of the transcription factor Ets1. Here, we show that, in breast cancer cells, Ets1 regulates Rho-GDIβ expression and binds to the upstream region of the <i>Rho-GDIβ</i> gene. Furthermore, in primary breast cancer, Rho-GDIβ is coexpressed with Ets1. Studying the function of Rho-GDIβ in breast cancer, we found that a Rho-GDIβ–specific small interfering RNA increased cellular migration but also decreased the expression of <i>cyclooxygenase-2 (Cox-2)</i> oncogene as shown by microarray, quantitative reverse transcription-PCR, and Western blot analyses. Further studies revealed that Rho-GDIβ regulates <i>Cox-2</i> 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-GDIβ, was also found to interfere with Cox-2 expression and NFAT-1 cellular distribution, suggesting a cooperative action of Rho-GDIβ and Vav-1 on Cox-2 expression. To explore the importance of Rho-GDIβ for the survival of breast cancer patients, two cohorts, including 263 and 117 patients, were analyzed for clinical outcome in relation to Rho-GDIβ RNA and protein levels, respectively. Expression of Rho-GDIβ was not associated with either disease-free or overall survival in the two patient population. Our data suggest that the expression of Rho-GDIβ in breast cancer is neither beneficial nor disadvantageous to the patient. This may be the net effect of two opposing activities of Rho-GDIβ, 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]</p></div>

Supplementary Figure 2 from <i>Cyclooxygenase-2</i> Is a Target Gene of Rho GDP Dissociation Inhibitor β in Breast Cancer Cells

Supplementary Tables 1-5 from <i>Cyclooxygenase-2</i> Is a Target Gene of Rho GDP Dissociation Inhibitor β in Breast Cancer Cells

Supplementary Figure 1 from <i>Cyclooxygenase-2</i> Is a Target Gene of Rho GDP Dissociation Inhibitor β in Breast Cancer Cells

Supplementary Figure 2 from <i>Cyclooxygenase-2</i> Is a Target Gene of Rho GDP Dissociation Inhibitor β in Breast Cancer Cells

Supplementary Figure 1 from <i>Cyclooxygenase-2</i> Is a Target Gene of Rho GDP Dissociation Inhibitor β in Breast Cancer Cells