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Series GSE18544 Query DataSets for GSE18544
Status Public on Oct 14, 2009
Title Expression Profiling of a Mouse Xenograft Model of “Triple-Negative” Breast Cancer Brain Metastases With Vorinostat
Organism Homo sapiens
Experiment type Expression profiling by array
Summary Gene Expression Profiling of a Mouse Xenograft Model of “Triple-Negative” Breast Cancer Brain Metastases With and Without Vorinostat Treatment.
Purpose: As chemotherapy and molecular therapy improve the systemic survival of breast cancer patients, the incidence of brain metastases increases. Few therapeutic strategies exist for the treatment of brain metastases because the blood-brain barrier severely limits drug access. We report the pharmacokinetic, efficacy, and mechanism of action studies for the histone deactylase inhibitor vorinostat (suberoylanilide hydroxamic acid) in a preclinical model of brain metastasis of triple-negative breast cancer.
Experimental Design: The 231-BR brain trophic subline of the MDA-MB-231 human breast cancer cell line was injected into immunocompromised mice for pharmacokinetic and metastasis studies. Pharmacodynamic studies compared histone acetylation, apoptosis, proliferation, and DNA damage in vitro and in vivo.
Results: Following systemic administration, uptake of [14C]vorinostat was significant into normal rodent brain and accumulation was up to 3-fold higher in a proportion of metastases formed by 231-BR cells. Vorinostat prevented the development of 231-BR micrometastases by 28% (P = 0.017) and large metastases by 62% (P < 0.0001) compared with vehicle-treated mice when treatment was initiated on day 3 post-injection. The inhibitory activity of vorinostat as a single agent was linked to a novel function in vivo: induction of DNA double-strand breaks associated with the down-regulation of the DNA repair gene Rad52.
Conclusions: We report the first preclinical data for the prevention of brain metastasis of triple-negative breast cancer. Vorinostat is brain permeable and can prevent the formation of brain metastases by 62%. Its mechanism of action involves the induction of DNA double-strand breaks, suggesting rational combinations with DNA active drugs or radiation.
Overall design We performed gene expression profiling on metastases from vehicle- or vorinostat-treated mice to determine if alterations in gene expression were observable that were consistent with the phenotypes observed. Brain metastases from five vehicle-treated mice and six 150 mg/kg vorinostat-treated mice were procured by laser capture microdissection. RNA was extracted from the captured tumor cells from each brain and two rounds of linear amplification was done. The amplified RNA from each mouse was processed separately through microarray hybridization and analysis.
Contributor(s) Davis S, Steeg PS, Meltzer PS, Palmieri D
Citation(s) 19789319
Submission date Oct 13, 2009
Last update date Dec 06, 2018
Contact name Sean Davis
Phone 301-435-2652
Organization name National Cancer Institute
Lab Genetics Branch
Street address 37 Convent Drive, Room 6138
City Bethesda
State/province MD
ZIP/Postal code 20892
Country USA
Platforms (1)
GPL571 [HG-U133A_2] Affymetrix Human Genome U133A 2.0 Array
Samples (11)
GSM461690 231-BR cells, vehicle treated, 66
GSM461691 231-BR cells, vehicle treated, 73
GSM461692 231-BR cells, vehicle treated, 83
BioProject PRJNA121351

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Supplementary file Size Download File type/resource
GSE18544_RAW.tar 18.2 Mb (http)(custom) TAR (of CEL)
Processed data included within Sample table

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