title: The SmgGDS splice variant SmgGDS-558 is a key promoter of tumor growth and RhoA signaling in breast cancer.
abstract: Breast cancer malignancy is promoted by the small GTPases RhoA and RhoC. SmgGDS is a guanine nucleotide exchange factor that activates RhoA and RhoC in vitro. We previously reported that two splice variants of SmgGDS, SmgGDS-607, and SmgGDS-558, have different characteristics in binding and transport of small GTPases. To define the role of SmgGDS in breast cancer, we tested the expression of SmgGDS in breast tumors, and the role of each splice variant in proliferation, tumor growth, Rho activation, and NF-κB transcriptional activity in breast cancer cells. We show upregulated SmgGDS protein expression in breast cancer samples compared with normal breast tissue. In addition, Kaplan-Meier survival curves indicated that patients with high SmgGDS expression in their tumors had worse clinical outcomes. Knockdown of SmgGDS-558, but not SmgGDS-607, in breast cancer cells decreased proliferation, in vivo tumor growth, and RhoA activity. Furthermore, we found that SmgGDS promoted a Rho-dependent activation of the transcription factor NF-κB, which provides a potential mechanism to define how SmgGDS-mediated activation of RhoA promotes breast cancer. This study demonstrates that elevated SmgGDS expression in breast tumors correlates with poor survival, and that SmgGDS-558 plays a functional role in breast cancer malignancy. Taken together, these findings define SmgGDS-558 as a unique promoter of RhoA and NF-κB activity and a novel therapeutic target in breast cancer.
  
  
  CONCLUSIONS
  This study defines a new mechanism to regulate the activities of RhoA and NF-κB in breast cancer cells, and identifies SmgGDS-558 as a novel promoter of breast cancer malignancy.
authors.affiliation: Department of Pharmacology and Toxicology, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI 53226. williams@mcw.edu.
authors.forename: Andrew D
authors.initials: AD
authors.lastname: Hauser
authors.forename: Carmen
authors.initials: C
authors.lastname: Bergom
authors.forename: Nathan J
authors.initials: NJ
authors.lastname: Schuld
authors.forename: Xiuxu
authors.initials: X
authors.lastname: Chen
authors.forename: Ellen L
authors.initials: EL
authors.lastname: Lorimer
authors.forename: Jian
authors.initials: J
authors.lastname: Huang
authors.forename: Alexander C
authors.initials: AC
authors.lastname: Mackinnon
authors.forename: Carol L
authors.initials: CL
authors.lastname: Williams
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000235:genetics* / Q000401:mortality; D002285:Carcinoma, Intraductal, Noninfiltrating / Q000235:genetics* / Q000401:mortality; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic / Q000235:genetics; D005260:Female; D020662:Guanine Nucleotide Exchange Factors / Q000096:biosynthesis / Q000235:genetics*; D006801:Humans; D053208:Kaplan-Meier Estimate; D061986:MCF-7 Cells; D051379:Mice; D016513:Mice, SCID; D016328:NF-kappa B / Q000235:genetics*; D009368:Neoplasm Transplantation; D011379:Prognosis; D011485:Protein Binding / Q000235:genetics; D020033:Protein Isoforms / Q000235:genetics; D021381:Protein Transport / Q000235:genetics; D034622:RNA Interference; D012326:RNA Splicing; D012333:RNA, Messenger / Q000096:biosynthesis; D034741:RNA, Small Interfering; D015398:Signal Transduction / Q000235:genetics; D014158:Transcription, Genetic; D014183:Transplantation, Heterologous; D020741:rho GTP-Binding Proteins / Q000235:genetics / Q000378:metabolism; D020742:rhoA GTP-Binding Protein / Q000235:genetics* / Q000378:metabolism; D000075024:rhoC GTP-Binding Protein
chemical_list: D020662:Guanine Nucleotide Exchange Factors; D016328:NF-kappa B; D020033:Protein Isoforms; C115955:RAP1GDS1 protein, human; D012333:RNA, Messenger; D034741:RNA, Small Interfering; C066690:RHOC protein, human; D020741:rho GTP-Binding Proteins; D020742:rhoA GTP-Binding Protein; D000075024:rhoC GTP-Binding Protein