Although multifactorial in origin, one of the most impactful consequences of social isolation is an increase in
breast cancer mortality. How this happens is unknown, but many studies have shown that social isolation increases circulating inflammatory
cytokines and impairs mitochondrial metabolism. Using a preclinical Sprague Dawley rat model of
estrogen receptor-positive
breast cancer, we investigated whether social isolation impairs the response to
tamoxifen therapy and increases the risk of
tumors emerging from dormancy, and thus their recurrence. We also studied which signaling pathways in the mammary glands may be affected by social isolation in
tamoxifen treated rats, and whether an anti-inflammatory herbal mixture blocks the effects of social isolation. Social isolation increased the risk of dormant mammary
tumor recurrence after
tamoxifen therapy. The elevated recurrence risk was associated with changes in multiple signaling pathways including an upregulation of
IL6/JAK/STAT3 signaling in the mammary glands and
tumors and suppression of the mitochondrial oxidative phosphorylation (OXPHOS) pathway. In addition, social isolation increased the expression of
receptor for advanced glycation end-products (RAGE), consistent with impaired
insulin sensitivity and
weight gain linked to social isolation. In socially isolated animals, the herbal product inhibited
IL6/JAK/STAT3 signaling, upregulated OXPHOS signaling, suppressed the expression of RAGE
ligands S100a8 and S100a9, and prevented the increase in recurrence of dormant mammary
tumors. Increased
breast cancer mortality among socially isolated survivors may be most effectively prevented by focusing on the period following the completion of
hormone therapy using interventions that simultaneously target several different pathways including inflammatory and mitochondrial metabolism pathways.