A Model of Gene-Environment Interaction Reveals Altered Mammary Gland Gene Expression and Increased Tumor Growth following Social Isolation

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.

Neonatal Experiences Differentially Influence Mammary Gland Morphology, Estrogen Receptor α Protein Levels, and Carcinogenesis in BALB/c Mice

“…Thus, the postpubertal increase in mammary gland ERα protein levels may have been amplified in LMS mice (relative to BMS and TR mice) due to altered HPG axis functioning. Previous studies using postpubertal social isolation as a stressor have shown stress-related effects on mammary tumorigenesis despite unaltered ERα protein levels (37,38). It is clear that the perceived intensity and the timing of the stressor with respect to development are important factors that modulate the effects of stress on mammary tumor risk.…”

Beta-Blocker Use Is Associated With Improved Relapse-Free Survival in Patients With Triple-Negative Breast Cancer

“…12,[26][27][28] Patients with TNBC have limited therapeutic options after completion of conventional chemotherapy. They suffer higher rates of relapse compared with patients with ER-positive breast cancer, with most recurrences occurring within the first 3 years of breast cancer diagnosis.…”

Stressing the need to overcome EGFR tyrosine kinase inhibitor resistance

“…Moreover, first generation beta-blockers targeting both the β1 and β2 adrenergic receptors, while second generation drugs mainly target just β1 (this subtype is primarily expressed on the myocardium) which could have also confounded conclusions. Evidence from experimental studies suggests that psychological stress can drive metastasis (18)(19)(20)(21)(22)(23)(24). For example, when mice bearing human tumors were confined or isolated from other miceconditions that increase stress-their tumors were more likely to metastasize.…”