| Loss of Rho GDIα and resistance to tamoxifen via effects on estrogen receptor α. | |
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MedLine Citation:
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PMID: 21447808 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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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. |
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Authors:
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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:
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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:
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Title: Journal of the National Cancer Institute Volume: 103 ISSN: 1460-2105 ISO Abbreviation: J. Natl. Cancer Inst. Publication Date: 2011 Apr |
Date Detail:
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Created Date: 2011-04-06 Completed Date: 2011-05-31 Revised Date: 2013-05-24 |
Medline Journal Info:
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Nlm Unique ID: 7503089 Medline TA: J Natl Cancer Inst Country: United States |
Other Details:
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Languages: eng Pagination: 538-52 Citation Subset: IM |
Affiliation:
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Lester and Sue Smith Breast Center, Breast Center, Baylor College of Medicine, Houston, TX 77479, USA. |
Export Citation:
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APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
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Animals Antineoplastic Agents, Hormonal / pharmacology*, therapeutic use Breast Neoplasms / metabolism*, prevention & control* Cell Line, Tumor Down-Regulation Drug Resistance, Neoplasm* / drug effects, genetics Enzyme Activation Estrogen Antagonists / pharmacology*, therapeutic use Estrogen Receptor alpha / drug effects, metabolism* Female Gene Expression Regulation, Neoplastic Gene Silencing Genome-Wide Association Study Guanine Nucleotide Dissociation Inhibitors / genetics, metabolism* Histone Deacetylases / genetics, metabolism* Humans Immunoblotting Immunohistochemistry Immunoprecipitation Mice Mice, Nude Neoplasm Recurrence, Local / metabolism, prevention & control* Odds Ratio Phenotype Plasmids 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 | |
ID/Acronym/Agency:
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P01 CA30195/CA/NCI NIH HHS; P50 CA58183/CA/NCI NIH HHS; R01 CA072038-15/CA/NCI NIH HHS; R01 CA72038/CA/NCI NIH HHS |
| Chemical | |
Reg. No./Substance:
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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; 10540-29-1/Tamoxifen; EC 3.5.1.-/MTA2 protein, human; EC 3.5.1.98/Histone Deacetylases; EC 3.6.5.2/rho GTP-Binding Proteins |
| Comments/Corrections | |
Comment In:
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J Natl Cancer Inst. 2011 Apr 6;103(7):526-7
[PMID:
21447809
]
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From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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