Chronic Social Isolation Is Associated with Metabolic Gene Expression Changes Specific to Mammary Adipose Tissue

Abstract

Chronic social isolation is linked to increased mammary tumor growth in rodent models of breast cancer. In the C3(1)/SV40 T-antigen FVB/N (TAg) mouse model of “triple-negative” breast cancer, the heightened stress response elicited by social isolation has been associated with increased expression of metabolic genes in the mammary gland before invasive tumors develop (i.e. during the in situ carcinoma stage). To further understand the mechanisms underlying how accelerated mammary tumor growth is associated with social isolation, we separated the mammary gland adipose tissue from adjacent ductal epithelial cells and analyzed individual cell types for changes in metabolic gene expression. Specifically, increased expression of the key metabolic genes Acaca, Hk2 and Acly was found in the adipocyte, rather than the epithelial fraction. Surprisingly, metabolic gene expression was not significantly increased in visceral adipose depots of socially isolated female mice. As expected, increased metabolic gene expression in the mammary adipocytes of socially isolated mice coincided with increased glucose metabolism, lipid synthesis, and leptin secretion from this adipose depot. Furthermore, application of media that had been cultured with isolated mouse mammary adipose tissue (conditioned media) resulted in increased proliferation of mammary cancer cells relative to group-housed conditioned media. These results suggest that exposure to a chronic stressor (social isolation) results in specific metabolic reprogramming in mammary gland adipocytes that in turn contributes to increased proliferation of adjacent pre-invasive malignant epithelial cells. Metabolites and/or tumor growth-promoting proteins secreted from adipose tissue could identify biomarkers and/or targets for preventive intervention in breast cancer.

Differential Brain, Cognitive and Motor Profiles Associated with Partial Trisomy. Modeling Down Syndrome in Mice

“…Males with B6.FVB background display aggressive behavior and they could not be housed together. Social isolation generates undesirable physiological and brain effects that can be permanent (Volden et al 2013 ). Each male to be tested was housed with a female to avoid these biases.…”

Mammary Adipose Tissue-Derived Lysophospholipids Promote Estrogen Receptor–Negative Mammary Epithelial Cell Proliferation

“…We previously reported that the chronic stressor of early social isolation is associated with increased metabolic gene expression of several genes encoding important glucose flux and lipid metabolism proteins (hexokinase 2, ATP citrate lyase, and acetyl-CoA carboxylase alpha) within the mammary adipocytes of 15 week old female mice (12). Increased expression of these particular enzymes was predicted to increase glucose flux into lipid synthesis, which was confirmed (12).…”

“…We previously reported that exposure to this form of chronic social stress is also associated with upregulation of genes mediating conversion of glucose to lipids in mammary adipocytes of female SV40 TAg mice, and a concomitant increase in de novo lipid synthesis (12). Furthermore, serum-free medium pre-incubated with mammary fat (conditioned medium) caused significantly augmented proliferation of Tag mouse mammary epithelial cells (MECs) (12). These data suggested that alterations in mammary adipocyte metabolism and associated changes in the mammary fat secretome could alter the local microenvironment and contribute to TNBC progression.…”

Sympathetic innervation, norepinephrine content, and norepinephrine turnover in orthotopic and spontaneous models of breast cancer

“…Sympathetic innervation was detected during premalignancy, coursing amongst adipocytes. This finding raises the possibility that SNS hardwiring of mammary adipose tissue is a mechanism by which catecholamines can regulate adipocytes and, mammary adipose tissue metabolism to modulate early mammary tumor progression (Volden et al, 2013; Zhang et al, 2009). The sparse TH+ sympathetic innervation detected in late-stage adenocarcinoma reflects the restricted distribution of sympathetic innervation to blood vessels and smooth muscle in the normal mammary gland (Eriksson et al Neuroscience, 1996).…”