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Altered mouse mammary gland gene expression and tumor growth following chronic social isolation

ABSTRACT: Clinical studies have revealed that social support improves the outcome of cancer patients while epidemiological studies suggest that social isolation increases the risk of death associated with several chronic diseases. However, the precise biological consequences of an unfavorable social environment have not been defined. To do so, robust, reproducible pre-clinical models are needed to study the mechanisms whereby an adverse environment impacts on gene expression and cancer biology. Because random assignment of inbred laboratory mice to well-defined social environments allows accurate and repeated measurements of behavioral and endocrine parameters, transgenic mice provide a pre-clinical framework with which to begin to determine gene-environment mechanisms. In this study, we found that female C3(1)/SV40 T-antigen mice deprived of social interaction from weaning exhibited increased expression of genes encoding key metabolic pathway enzymes in the pre-malignant mammary gland. Chronic social isolation was associated with upregulated fatty acid synthesis and glycolytic pathway gene expression - both pathways known to contribute to increased breast cancer growth. Consistent with the expression of metabolic genes, isolated mice subsequently developed significantly larger mammary gland tumors compared to group-housed mice. Endocrine evaluation confirmed that isolated mice developed a heightened corticosterone stress response compared to group-housed mice. Together, these transdisciplinary studies show for the first time that an adverse social environment is associated with altered mammary gland gene expression and tumor growth. Moreover, the identification of specific alterations in metabolic pathways favoring tumor growth suggests potential molecular biomarkers and/or targets (e.g. fatty acid synthesis) for preventive intervention in breast cancer.

ORGANISM(S): Mus musculus

PROVIDER: GSE16110 | GEO | 2009/07/01

SECONDARY ACCESSION(S): PRJNA117223

REPOSITORIES: GEO

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Project description:Clinical studies have revealed that social support improves the outcome of cancer patients while epidemiological studies suggest that social isolation increases the risk of death associated with several chronic diseases. However, the precise biological consequences of an unfavorable social environment have not been defined. To do so, robust, reproducible pre-clinical models are needed to study the mechanisms whereby an adverse environment impacts on gene expression and cancer biology. Because random assignment of inbred laboratory mice to well-defined social environments allows accurate and repeated measurements of behavioral and endocrine parameters, transgenic mice provide a pre-clinical framework with which to begin to determine gene-environment mechanisms. In this study, we found that female C3(1)/SV40 T-antigen mice deprived of social interaction from weaning exhibited increased expression of genes encoding key metabolic pathway enzymes in the pre-malignant mammary gland. Chronic social isolation was associated with upregulated fatty acid synthesis and glycolytic pathway gene expression - both pathways known to contribute to increased breast cancer growth. Consistent with the expression of metabolic genes, isolated mice subsequently developed significantly larger mammary gland tumors compared to group-housed mice. Endocrine evaluation confirmed that isolated mice developed a heightened corticosterone stress response compared to group-housed mice. Together, these transdisciplinary studies show for the first time that an adverse social environment is associated with altered mammary gland gene expression and tumor growth. Moreover, the identification of specific alterations in metabolic pathways favoring tumor growth suggests potential molecular biomarkers and/or targets (e.g. fatty acid synthesis) for preventive intervention in breast cancer. Experiment Overall Design: SV40 Tag mice we isolated or grouped at weaning. Mouse mammary glands were rapidly excised at necropsy and immediatley flash frozen to detect difference in gene expression between thoraci MG from isolated versus group-housed female mice.

Project description:Social stress is well known to be involved in the occurrence and exacerbation of mental illness, and also various life-style related diseases such as hyperinsulinemia, hyperglycemia, cardiovascular diseases and cancer. However, there is little information on tissue-specific gene expression in response to social stress, which reflects our daily life. Liver is one of the most important organs, owing to its biological functions such as energy metabolic homeostasis, metabolization and detoxification of endo- and exogenous substances. In order to elucidate the mechanism underlying response to social stress in the liver, we investigated hepatic gene expression in mice exposed to isolation stress using DNA microarray. Male BALB/c mice (4 weeks old) were housed 5 per cage for 10 days acclimatization. Then mice were exposed to isolation stress for 30 days. After stress treatment, the mouse liver RNA was subjected to DNA microarray analysis. Taking the false discovery rate into account, isolation stress altered expression of 420 genes. Moreover, Gene Ontology analysis of these differentially expressed genes indicated that isolation stress remarkably down-regulated lipid metabolism-related pathway through peroxisome proliferator-activated receptor-ï¡ (PPARï¡), while lipid biosynthesis pathway regulated by sterol regulatory element binding factor-1 (SREBF-1), Golgi vesicle transport and secretory pathway-related genes were significantly up-regulated. These results suggested that isolation for 30 days, mild and consecutive social stress, not only regulate the systems for lipid metabolism but also cause the endoplasmic reticulum stress in mouse liver. Experiment Overall Design: Male BALB/c mice (4 weeks old, Japan SLC, Shizuoka, Japan) weighing 14-18 g were housed 5 per cage. After acclimatization for 10 days, the mice were exposed to isolation (1 mouse per cage). All cages were placed in a foam plastic box in order to avoid social contact. To enhance the feeling of isolation, the bed volume in each cage for the isolated mice was reduced to one-tenth of that in the control group. The weight of bedding chips was about 2 g. All mice were housed in an air-conditioned room ( room temperature: 23 Â± 1Â°C, humidity: 55 Â± 5 %) under 12 h dark/12 h light cycles, with free access to tap water and MF diet (Oriental Yeast Co., Tokyo, Japan).

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Altered mouse mammary gland gene expression and tumor growth following chronic social isolation

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