title: Rac3 induces a molecular pathway triggering breast cancer cell aggressiveness: differences in MDA-MB-231 and MCF-7 breast cancer cell lines.
abstract: BACKGROUND
  Rho GTPases are involved in cellular functions relevant to cancer. The roles of RhoA and Rac1 have already been established. However, the role of Rac3 in cancer aggressiveness is less well understood.
  
  
  METHODS
  This work was conducted to analyze the implication of Rac3 in the aggressiveness of two breast cancer cell lines, MDA-MB-231 and MCF-7: both express Rac3, but MDA-MB-231 expresses more activated RhoA. The effect of Rac3 in cancer cells was also compared with its effect on the non-tumorigenic mammary epithelial cells MCF-10A. We analyzed the consequences of Rac3 depletion by anti-Rac3 siRNA.
  
  
  RESULTS
  Firstly, we analyzed the effects of Rac3 depletion on the breast cancer cells' aggressiveness. In the invasive MDA-MB-231 cells, Rac3 inhibition caused a marked reduction of both invasion (40%) and cell adhesion to collagen (84%), accompanied by an increase in TNF-induced apoptosis (72%). This indicates that Rac3 is involved in the cancer cells' aggressiveness. Secondly, we investigated the effects of Rac3 inhibition on the expression and activation of related signaling molecules, including NF-κB and ERK. Cytokine secretion profiles were also analyzed. In the non-invasive MCF-7 line; Rac3 did not influence any of the parameters of aggressiveness.
  
  
  CONCLUSIONS
  This discrepancy between the effects of Rac3 knockdown in the two cell lines could be explained as follows: in the MDA-MB-231 line, the Rac3-dependent aggressiveness of the cancer cells is due to the Rac3/ERK-2/NF-κB signaling pathway, which is responsible for MMP-9, interleukin-6, -8 and GRO secretion, as well as the resistance to TNF-induced apoptosis, whereas in the MCF-7 line, this pathway is not functional because of the low expression of NF-κB subunits in these cells. Rac3 may be a potent target for inhibiting aggressive breast cancer.
authors: Laboratoire MERCI - EA3829, Faculté de Médecine et de Pharmacie, Université de Rouen, Rouen, France. caroline.gest@yahoo.fr
authors: Caroline
authors: C
authors: Gest
authors: Ulrich
authors: U
authors: Joimel
authors: Limin
authors: L
authors: Huang
authors: Linda-Louise
authors: LL
authors: Pritchard
authors: Alexandre
authors: A
authors: Petit
authors: Charlène
authors: C
authors: Dulong
authors: Catherine
authors: C
authors: Buquet
authors: Chao-Quan
authors: CQ
authors: Hu
authors: Pezhman
authors: P
authors: Mirshahi
authors: Marc
authors: M
authors: Laurent
authors: Françoise
authors: F
authors: Fauvel-Lafève
authors: Lionel
authors: L
authors: Cazin
authors: Jean-Pierre
authors: JP
authors: Vannier
authors: He
authors: H
authors: Lu
authors: Jeannette
authors: J
authors: Soria
authors: Hong
authors: H
authors: Li
authors: Rémi
authors: R
authors: Varin
authors: Claudine
authors: C
authors: Soria
mesh_terms: D017209:Apoptosis; D001943:Breast Neoplasms / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D002448:Cell Adhesion; D002465:Cell Movement; D048430:Cell Shape; D002470:Cell Survival; D003094:Collagen / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005260:Female; D006801:Humans; D061986:MCF-7 Cells; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D009361:Neoplasm Invasiveness; D034622:RNA Interference; D015398:Signal Transduction; D013997:Time Factors; D014162:Transfection; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D020744:rac GTP-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D020742:rhoA GTP-Binding Protein / Q000378:metabolism
chemical_list: D016207:Cytokines; D016328:NF-kappa B; C411563:RAC3 protein, human; D014409:Tumor Necrosis Factor-alpha; C066737:RHOA protein, human; D003094:Collagen; D048049:Extracellular Signal-Regulated MAP Kinases; C579270:MMP9 protein, human; D020780:Matrix Metalloproteinase 9; D020744:rac GTP-Binding Proteins; D020742:rhoA GTP-Binding Protein
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