Homo sapiens
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PROVIDER: PRJNA121351 | ENA |
REPOSITORIES: ENA
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Project description:Gene Expression Profiling of a Mouse Xenograft Model of â??Triple-Negativeâ?? 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. Experiment 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.
2009-10-27 | E-GEOD-18544 | biostudies-arrayexpress
Project description: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.
2009-10-14 | GSE18544 | GEO
Project description:Breast cancer in young patients is known to exhibit more aggressive biological behavior and is associated with a less favorable prognosis than the same disease in older patients, owing in part to an increased incidence of brain metastases, the mechanistic explanations behind which remain poorly understood. We recently reported that young mice, compared to older mice, showed about a three-fold increase in the development of brain metastases in mouse models of triple-negative and luminal B breast cancer. Here we have performed a quantitative mass spectrometry-based proteomic analysis to identify proteins contributing to age-related disparities in the development of breast cancer brain metastases. Using a mouse model of brain-tropic (MDA-MB-231BR) triple-negative breast cancer, we harvested subpopulations of tumor metastases, the tumor-adjacent metastatic microenvironment, and uninvolved brain tissues via laser microdissection followed by quantitative proteomic analysis using high resolution mass spectrometry to characterize differentially abundant proteins contributing to age-dependent rates of brain metastasis.
2024-01-11 | PXD042346 | Pride
Project description:Background: Metastases to the brain from breast cancer have a high mortality. Basal-like and HER2 positive breast cancers appear to have a high propensity to spread to the brain. The mechanisms that allow cells to colonise the brain are unclear. Methods: We have analysed matched and unpaired samples of breast cancer and brain metastases using morphology, immunophenotype and expression profiling and validated the data using in vitro cell culturing models and in vivo mice model. Results: Most of the brain metastases were triple negative and had a basal-like phenotype. Metastatic cells to the brain over-expressed HER3 compared to primaries and showed evidence of higher activation of the MAPK pathways. Inhibition using anti-neuregulin antibody, Herceptin and Lapatinib reduced tumour growth in vitro and in vivo. Conclusions: The data demonstrate activation of neuregulin-HER3 pathway in brain metastases from breast cancer and suggest that even in absence of HER2 amplification (as with triple negative and basal cancers), anti-epidermal growth factor receptor family inhibitors may have a role in treating these patients.
2009-02-11 | GSE14683 | GEO
Project description:Background: Metastases to the brain from breast cancer have a high mortality. Basal-like and HER2 positive breast cancers appear to have a high propensity to spread to the brain. The mechanisms that allow cells to colonise the brain are unclear. Methods: We have analysed matched and unpaired samples of breast cancer and brain metastases using morphology, immunophenotype and expression profiling and validated the data using in vitro cell culturing models and in vivo mice model. Results: Most of the brain metastases were triple negative and had a basal-like phenotype. Metastatic cells to the brain over-expressed HER3 compared to primaries and showed evidence of higher activation of the MAPK pathways. Inhibition using anti-neuregulin antibody, Herceptin and Lapatinib reduced tumour growth in vitro and in vivo. Conclusions: The data demonstrate activation of neuregulin-HER3 pathway in brain metastases from breast cancer and suggest that even in absence of HER2 amplification (as with triple negative and basal cancers), anti-epidermal growth factor receptor family inhibitors may have a role in treating these patients
2009-02-11 | GSE14682 | GEO
Project description:We used single-cell RNA-sequencing to investigate the role of myeloid cells in a humanized mouse model of breast cancer brain metastasis (BCBM). We generated brain metastases with a cardiac-injection of the human triple-negative breast cancer cell line MDA-MB-231BR2 (231BR) into MITRG mice and allowed tumors to grow in the brain for 25 days. We then took all human cells (includes myeloid cells and 231BR) from these mice verses control MITRG brains (only myeloid cells) to find transcriptional changes associated with BCBM.
2023-09-01 | GSE147948 | GEO
Project description:We used single-cell RNA-sequencing to investigate the role of brain-resident microglia versus infiltrating cells in a mouse model of breast cancer brain metastasis (BCBM). We generated brain metastases with a cardiac-injection of the human triple-negative breast cancer cell line MDA-MB-231BR2 (231BR) into Foxn1 nu/nu mice and allowed tumors to grow in the brain for four weeks. We then compared astrocytes (ASCA2+CD45-) and myeloid cells (CD11b+CD45+) from these mice verses control Foxn1 nu/nu brains to find transcriptional changes associated with BCBM.
2023-09-01 | GSE147942 | GEO
Project description:We report the development of MULTI-seq: a scRNA-seq and snRNA-seq sample multiplexing approach using lipid- or cholesterol-modified oligonucleotides. We demonstrate MULTI-seq utility in the following scRNA-seq and snRNA-seq contexts: (1) Live HEKs and HMECs with and without stimulation with TGF-β, (2) Purified nuclei from HEKs, MEFs, and Jurkats stimulated for 0-24 hrs with ionomycin and PMA, (3) 96 unique HMEC cultures (with one technical replicate), and (4) human metastases and mouse immune cells isolated from cryopreserved primary tissue samples dissected from a patient-derived xenograft mouse model of triple-negative breast cancer at progressive stages of metastasis to the lung.
2019-04-11 | GSE129578 | GEO
Project description:Single cell transcriptomes of brain metastases and micrometastases derived from triple negative human breast cancer cell line in mouse model.
| PRJNA640555 | ENA
Project description:Genetically-engineered mouse triple-negative breast cancer model was treated with Zotatifin for three days before tandem mass tag mass spectrometry (TMT-MS) analysis.
2022-06-01 | MSV000089580 | MassIVE