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.
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Authors | Kenneth L van Golen, LiWei Bao, Melinda M DiVito, ZhiFen Wu, George C Prendergast, Sofia D Merajver |
Journal | Molecular cancer therapeutics
(Mol Cancer Ther)
Vol. 1
Issue 8
Pg. 575-83
(Jun 2002)
ISSN: 1535-7163 [Print] United States |
PMID | 12479217
(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.)
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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
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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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