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The murine metastatic microenvironment of experimental brain metastases in breast cancer differs by host age in vivo: A proteomic study.

ABSTRACT: 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.

INSTRUMENT(S): Q Exactive

ORGANISM(S): Homo Sapiens (human) Mus Musculus (mouse)

TISSUE(S): Brain, Epithelial Cell, Stroma

DISEASE(S): Breast Cancer

SUBMITTER: Thomas Conrads

LAB HEAD: Thomas P. Conrads

PROVIDER: PXD042346 | Pride | 2024-01-11

REPOSITORIES: Pride

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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.

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The murine metastatic microenvironment of experimental brain metastases in breast cancer differs by host age in vivo: A proteomic study.

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