Reversion of RhoC GTPase-induced inflammatory breast cancer phenotype by treatment with a farnesyl transferase inhibitor.
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.
van Golen
Kenneth L
KL
Department of Internal Medicine, Division of Hematology/Oncology, University of Michigan, Ann Arbor, Michigan 48109, USA.
Bao
LiWei
L
DiVito
Melinda M
MM
Wu
ZhiFen
Z
Prendergast
George C
GC
Merajver
Sofia D
SD
D019883:Alkyl and Aryl Transferases / Q000037:antagonists & inhibitors*; D017209:Apoptosis; D015153:Blotting, Western; D001943:Breast Neoplasms / Q000201:enzymology* / Q000378:metabolism*; D002455:Cell Division; D002461:Cell Line, Transformed; D002465:Cell Movement; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D051231:Farnesyltranstransferase; D006801:Humans; D008715:Methionine / Q000031:analogs & derivatives* / Q000494:pharmacology*; D008855:Microscopy, Electron, Scanning; D008856:Microscopy, Fluorescence; D010590:Phalloidine / Q000494:pharmacology; D010641:Phenotype; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012235:Rhodamines / Q000494:pharmacology; D014162:Transfection; D014407:Tumor Cells, Cultured; D020741:rho GTP-Binding Proteins / Q000378:metabolism*; D000075024:rhoC GTP-Binding Protein
D004791:Enzyme Inhibitors; C096898:L 744832; D012235:Rhodamines; D010590:Phalloidine; D008715:Methionine; D019883:Alkyl and Aryl Transferases; D051231:Farnesyltranstransferase; C066690:RHOC protein, human; D020741:rho GTP-Binding Proteins; D000075024:rhoC GTP-Binding Protein