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Reversion of RhoC GTPase-induced inflammatory breast cancer phenotype by treatment with a farnesyl transferase inhibitor.

Abstract
Inflammatory breast carcinoma (IBC) is a highly aggressive form of locally advanced breast cancer that has the ability to invade and block the dermal lymphatics of the skin overlying the breast. In a previous series of studies, our laboratory identified overexpression of RhoC GTPase in >90% of IBCs (K. L. van Golen et al., Clin. Cancer Res., 5: 2511-2519, 1999) and defined RhoC as a mammary oncogene involved in conferring the metastatic phenotype (K. L. van Golen et al., Cancer Res., 60: 5832-5838, 2000). RhoC GTPase is involved in cytoskeletal reorganization during cellular motility. Farnesyl transferase inhibitors (FTIs) were previously shown to be effective in modulating tumor growth in Ras-transformed tumor cells. Recently, studies have focused on RhoB as a putative non-Ras target of FTI action. In the present study, we assessed the effect of the FTI L-744,832 on RhoC-overexpressing IBC and RhoC-transfected human mammary epithelial (HME-RhoC) cells. Treatment of the SUM149 IBC cell line and HME-RhoC transfectants with the FTI L-744,832 led to reversion of the RhoC-induced phenotype, manifested by a significant decrease in anchorage-independent growth, motility, and invasion. Although RhoC expression and activation were not affected, RhoB levels were increased by FTI treatment. Transient transfection of geranylgeranylated RhoB (RhoB-GG) into the same cells reproduced the effects of the FTI, thus suggesting that FTI-induced reversion of the RhoC phenotype may be mediated by an increase in RhoB-GG levels. These data provide direct evidence that FTIs may find use in the clinic when directed against RhoC-overexpressing tumors and suggest appropriate biological markers to evaluate during FTI treatment.
AuthorsKenneth L van Golen, LiWei Bao, Melinda M DiVito, ZhiFen Wu, George C Prendergast, Sofia D Merajver
JournalMolecular cancer therapeutics (Mol Cancer Ther) Vol. 1 Issue 8 Pg. 575-83 (Jun 2002) ISSN: 1535-7163 [Print] United States
PMID12479217 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S., Research Support, U.S. Gov't, P.H.S.)
Chemical References
  • Enzyme Inhibitors
  • L 744832
  • Rhodamines
  • Phalloidine
  • Methionine
  • Alkyl and Aryl Transferases
  • Farnesyltranstransferase
  • RHOC protein, human
  • rho GTP-Binding Proteins
  • rhoC GTP-Binding Protein
Topics
  • Alkyl and Aryl Transferases (antagonists & inhibitors)
  • Apoptosis
  • Blotting, Western
  • Breast Neoplasms (enzymology, metabolism)
  • Cell Division
  • Cell Line, Transformed
  • Cell Movement
  • Enzyme Inhibitors (pharmacology)
  • Farnesyltranstransferase
  • Humans
  • Methionine (analogs & derivatives, pharmacology)
  • Microscopy, Electron, Scanning
  • Microscopy, Fluorescence
  • Phalloidine (pharmacology)
  • Phenotype
  • Reverse Transcriptase Polymerase Chain Reaction
  • Rhodamines (pharmacology)
  • Transfection
  • Tumor Cells, Cultured
  • rho GTP-Binding Proteins (metabolism)
  • rhoC GTP-Binding Protein

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