Document Detail

Loss of Rho GDIα and resistance to tamoxifen via effects on estrogen receptor α.
MedLine Citation:
PMID:  21447808     Owner:  NLM     Status:  MEDLINE    
BACKGROUND: Estrogen receptor (ER) α is a successful therapeutic target in breast cancer, but patients eventually develop resistance to antiestrogens such as tamoxifen.
METHODS: To identify genes whose expression was associated with the development of tamoxifen resistance and metastasis, we used microarrays to compare gene expression in four primary tumors from tamoxifen-treated patients whose breast cancers did not recur vs five metastatic tumors from patients whose cancers progressed during adjuvant tamoxifen treatment. Because Rho guanine dissociation inhibitor (GDI) α was underexpressed in the tamoxifen-resistant group, we stably transfected ERα-positive MCF-7 breast cancer cells with a plasmid encoding a short hairpin (sh) RNA to silence Rho GDIα expression. We used immunoblots and transcription assays to examine the role of Rho GDIα in ER-related signaling and growth of cells in vitro and as xenografts in treated nude mice (n = 8-9 per group) to examine the effects of Rho GDIα blockade on hormone responsiveness and metastatic behavior. The time to tumor tripling as the time in weeks from randomization to a threefold increase in total tumor volume over baseline was examined in treated mice. The associations of Rho GDIα and MTA2 levels with tamoxifen resistance were examined in microarray data from patients. All statistical tests were two-sided.
RESULTS: Rho GDIα was expressed at lower levels in ERα-positive tumors that recurred during tamoxifen treatment than in ERα-positive tamoxifen-sensitive primary tumors. MCF-7 breast cancer cells in which Rho GDIα expression had been silenced were tamoxifen-resistant, had increased Rho GTPase and p21-activated kinase 1 activity, increased phosphorylation of ERα at serine 305, and enhanced tamoxifen-induced ERα transcriptional activity compared with control cells. MCF-7 cells in which Rho GDIα expression was silenced metastasized with high frequency when grown as tumor xenografts. When mice were treated with estrogen or estrogen withdrawal, tripling times for xenografts from cells with Rho GDIα silencing were similar to those from vector-containing control cells; however, tripling times were statistically significantly faster than control when mice were treated with tamoxifen (median tripling time for tumors with Rho GDIα small interfering RNA = 2.34 weeks; for control tumors = not reached, hazard ratio = 4.13, 95% confidence interval = 1.07 to 15.96, P = .040 [adjusted for multiple comparisons, P = .119]). Levels of the metastasis-associated protein MTA2 were also increased upon Rho GDIα silencing, and combined Rho GDIα and MTA2 levels were associated with recurrence in 250 tamoxifen-treated patients.
CONCLUSION: Loss of Rho GDIα enhances metastasis and resistance to tamoxifen via effects on both ERα and MTA2 in models of ERα-positive breast cancer and in tumors of tamoxifen-treated patients.
Ines Barone; Lauren Brusco; Guowei Gu; Jennifer Selever; Amanda Beyer; Kyle R Covington; Anna Tsimelzon; Tao Wang; Susan G Hilsenbeck; Gary C Chamness; Sebastiano Andò; Suzanne A W Fuqua
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Publication Detail:
Type:  Comparative Study; Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, Non-P.H.S.     Date:  2011-03-29
Journal Detail:
Title:  Journal of the National Cancer Institute     Volume:  103     ISSN:  1460-2105     ISO Abbreviation:  J. Natl. Cancer Inst.     Publication Date:  2011 Apr 
Date Detail:
Created Date:  2011-04-06     Completed Date:  2011-05-31     Revised Date:  2014-09-12    
Medline Journal Info:
Nlm Unique ID:  7503089     Medline TA:  J Natl Cancer Inst     Country:  United States    
Other Details:
Languages:  eng     Pagination:  538-52     Citation Subset:  IM    
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MeSH Terms
Antineoplastic Agents, Hormonal / pharmacology*,  therapeutic use
Breast Neoplasms / metabolism*,  prevention & control*
Cell Line, Tumor
Drug Resistance, Neoplasm* / drug effects,  genetics
Enzyme Activation
Estrogen Antagonists / pharmacology*,  therapeutic use
Estrogen Receptor alpha / drug effects,  metabolism*
Gene Expression Regulation, Neoplastic
Gene Silencing
Genome-Wide Association Study
Guanine Nucleotide Dissociation Inhibitors / genetics,  metabolism*
Histone Deacetylases / genetics,  metabolism*
Mice, Nude
Neoplasm Recurrence, Local / metabolism,  prevention & control*
Odds Ratio
Protein Array Analysis
RNA, Small Interfering / metabolism
Random Allocation
Repressor Proteins / genetics,  metabolism*
Retrospective Studies
Secondary Prevention / methods
Selective Estrogen Receptor Modulators / pharmacology
Signal Transduction* / drug effects,  genetics
Tamoxifen / pharmacology*,  therapeutic use
Time Factors
Transcriptional Activation
Transplantation, Heterologous
Tumor Stem Cell Assay
rho GTP-Binding Proteins / metabolism
rho Guanine Nucleotide Dissociation Inhibitor alpha
rho-Specific Guanine Nucleotide Dissociation Inhibitors
Grant Support
Reg. No./Substance:
0/Antineoplastic Agents, Hormonal; 0/Arhgdia protein, mouse; 0/Estrogen Antagonists; 0/Estrogen Receptor alpha; 0/Guanine Nucleotide Dissociation Inhibitors; 0/RNA, Small Interfering; 0/Repressor Proteins; 0/Selective Estrogen Receptor Modulators; 0/rho Guanine Nucleotide Dissociation Inhibitor alpha; 0/rho-Specific Guanine Nucleotide Dissociation Inhibitors; 094ZI81Y45/Tamoxifen; EC 3.5.1.-/MTA2 protein, human; EC Deacetylases; EC GTP-Binding Proteins
Comment In:
J Natl Cancer Inst. 2011 Apr 6;103(7):526-7   [PMID:  21447809 ]

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