title: RhoGDI deficiency induces constitutive activation of Rho GTPases and COX-2 pathways in association with breast cancer progression.
abstract: Rho GDP Dissociation Inhibitor (RhoGDI) is a key regulator of Rho GTPases. Here we report that loss of RhoGDI significantly accelerated xenograft tumor growth of MDA-MB-231 cells in animal models. At the molecular level, RhoGDI depletion resulted in constitutive activation of Rho GTPases, including RhoA, Cdc42, and Rac1. This was accompanied by Rho GTPase translocation from the cytosol to membrane compartments. Notably, COX-2 protein levels, mRNA expression, and biological activity were markedly increased in RhoGDI-deficient cells. The upregulated expression of COX-2 was directly associated with increased Rho GTPase activity. Further, we assessed the expression level of RhoGDI protein in breast tumor specimens (n = 165) by immunohistochemistry. We found that RhoGDI expression is higher in the early stages of breast cancer followed by a significant decrease in malignant tumors and metastatic lesions (p < 0.01). These data suggest that downregulation of RhoGDI could be a critical mechanism of breast tumor development, which may involve the hyperactivation of Rho GTPases and upregulation of COX-2 activity. Additional studies are warranted to evaluate the therapeutic potential of inhibiting Rho GTPases and COX-2 for treating breast cancers.
authors.affiliation: Office of Biotechnology Products, Center for Drug Evaluation and Research, Food and Drug Administration, Silver Spring, MD 20993, USA.
authors.forename: William P
authors.initials: WP
authors.lastname: Bozza
authors.affiliation: Office of Biotechnology Products, Center for Drug Evaluation and Research, Food and Drug Administration, Silver Spring, MD 20993, USA.
authors.forename: Yaqin
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Office of Biotechnology Products, Center for Drug Evaluation and Research, Food and Drug Administration, Silver Spring, MD 20993, USA.
authors.forename: Kory
authors.initials: K
authors.lastname: Hallett
authors.affiliation: Office of Biotechnology Products, Center for Drug Evaluation and Research, Food and Drug Administration, Silver Spring, MD 20993, USA.|United States Public Health Service Commissioned Corps, Rockville, MD 20852, USA.
authors.forename: Leslie A
authors.initials: LA
authors.lastname: Rivera Rosado
authors.affiliation: Office of Biotechnology Products, Center for Drug Evaluation and Research, Food and Drug Administration, Silver Spring, MD 20993, USA.
authors.forename: Baolin
authors.initials: B
authors.lastname: Zhang
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002470:Cell Survival; D051546:Cyclooxygenase 2 / Q000235:genetics / Q000378:metabolism*; D018450:Disease Progression; D004789:Enzyme Activation; D005260:Female; D015971:Gene Expression Regulation, Enzymologic; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008819:Mice, Nude; D009367:Neoplasm Staging; D021381:Protein Transport; D034622:RNA Interference; D015398:Signal Transduction; D013997:Time Factors; D014162:Transfection; D047368:Tumor Burden; D020741:rho GTP-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D062948:rho Guanine Nucleotide Dissociation Inhibitor alpha / Q000172:deficiency* / Q000235:genetics
chemical_list: C569638:ARHGDIA protein, human; D062948:rho Guanine Nucleotide Dissociation Inhibitor alpha; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D020741:rho GTP-Binding Proteins
keywords: COX-2 activation; Rho GTPases; RhoGDI; breast cancer; tumor growth