A model of gene-environment interaction reveals altered mammary gland gene expression and increased tumor growth following social isolation
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Abstract
Clinical studies have revealed that social support improves the outcome of cancer patients, whereas epidemiologic studies suggest that social isolation increases the risk of death associated with several chronic diseases. However, the precise molecular consequences of an unfavorable social environment have not been defined. To do so, robust, reproducible preclinical models are needed to study the mechanisms whereby an adverse environment affects 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 preclinical 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 premalignant mammary gland. Chronic social isolation was associated with up-regulated lipid synthesis and glycolytic pathway gene expression—both pathways are known to contribute to increased breast cancer growth. Consistent with the expression of metabolic genes in premalignant mammary tissue, isolated mice subsequently developed a significantly larger mammary gland tumors burden compared with group-housed mice. Endocrine evaluation confirmed that isolated mice developed a heightened corticosterone stress response compared with 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 gene expression favoring tumor growth suggests potential molecular biomarkers and/or targets (e.g., fatty acid synthesis) for preventive intervention in breast cancer.
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Socially isolated animals show glucocorticoid-related increases in breast cancer burden, and molecular analyses find glucocorticoid signaling to promote cancer-related processes including mammary adipocyte metabolism, inhibition of tumor suppressor genes such as TP53, and resistance to chemotherapy-mediated programmed cell death.
“For example, socially isolated animals show glucocorticoid-related increases in breast cancer burden [46], [47], and molecular analyses find glucocorticoid signaling to promote several cancer-related processes including mammary adipocyte metabolism [47], [48], inhibition of tumor suppressor genes such as TP53 [49], and resistance to chemotherapy-mediated programmed cell death [50], [51].”
From Human Social Genomics (2014) · cites this paper as [47]
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- Authors
- Williams, J. B., Pang, D., Delgado, B., Kocherginsky, M., Tretiakova, M., Krausz, T., Pan, D., He, J., McClintock, M. K., & Conzen, S. D.
- Affiliations
- University of Chicago (US)
- Corresponding author
- Conzen, Suzanne D.
- ORCID
- Venue
- Cancer Prevention Research
- Published
- 2009-10-01
- Volume
- 2
- Issue
- 10
- Pages
- 850-861
- ISSN
- 1940-6207 (ISSN-L)
- 1940-6215
- PMC
- PMC4707045
- OpenAlex
- W2150351703
- Cited by
- 137
- References
- 52
- Citations by year
- 2026: 8 · 2025: 2 · 2024: 4 · 2023: 8 · 2022: 18 · 2021: 10 · 2020: 7 · 2019: 5 · 2018: 4 · 2017: 6 · 2016: 6 · 2015: 5 · 2014: 8 · 2013: 12 · 2012: 12
- FWCI
- 7.01
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Cancer Prevention Research (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- Northwestern University
- National Cancer Institute (R01CA089208, P30CA014599)
- National Institute of Environmental Health Sciences (P50ES012382)
- Topics
- Health Sciences › Medicine › Psychiatry and Mental health › Cancer, Stress, Anesthesia, and Immune Response
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Lipids, and Metabolism
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
- Keywords
- social isolation, gene-environment interaction, mammary gland gene expression, breast cancer, lipogenesis, glycolysis, metabolic pathways, corticosterone, stress response, transgenic mice, tumor growth, social environment, cancer prevention
- MeSH terms
- Animals, Cell Transformation, Neoplastic, Disease Models, Animal, Female, Immunohistochemistry, Mammary Glands, Animal, Mammary Neoplasms, Experimental, Mice, Transgenic, Precancerous Conditions, Social Isolation, Blotting, Western, Gene Expression, Gene Expression Regulation, Neoplastic, Reverse Transcriptase Polymerase Chain Reaction, Oligonucleotide Array Sequence Analysis, Mice
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