Increased risk of mammary cancer recurrence in socially isolated rats is linked to upregulation of IL6/JAK/STAT3 and inhibition of oxidative phosphorylation signaling, activities blocked by the herbal mixture Jaeumganghwa-tang. Increased risk of mammary cancer recurrence in socially isolated rats is linked to upregulation of IL6/JAK/STAT3 and inhibition of oxidative phosphorylation signaling, activities blocked by the herbal mixture Jaeumganghwa-tang

While multifactorial in origin, one of the most prevalent and impactful consequences of social isolation is an increase in cancer mortality. Using a preclinical model in Sprague Dawley rats, we found that social isolation increased the risk of mammary tumor recurrence after completion of antiestrogen therapy. The increased recurrence risk was associated with an upregulation of IL6/JAK/STAT3 signaling in the mammary glands and tumors and suppression of mitochondrial oxidative phosphorylation (OXPHOS) pathway. Also inhibited were genes involved in mitochondrial pyruvate transport and the conversion of pyruvate to acetyl CoA but lactate levels were not altered. In addition, social isolation increased the expression of receptor for advanced glycation end-products (RAGE), consistent with the impaired insulin sensitivity and weight gain linked to social isolation. All these changes are commonly associated with aging. In socially isolated animals consumption of the anti-inflammatory 12 herb mixture Jaeumganghwa-tang (JGT) inhibited IL6/JAK/STAT3 signaling, upregulated OXPHOS signaling, suppressed expression of the RAGE ligands S100a8 and S100a9, and prevented the increased risk of mammary cancer recurrence. In summary, increased breast cancer mortality among socially isolated survivors may be most effectively prevented by focusing on the period following the completion of endocrine therapy using tools that inhibit IL6/JAK/STAT3 inflammatory cytokine signaling and reverse disrupted OXPHOS. Overall design: Estrogen receptor positive (ER+) mammary tumors were induced in 50-day-old Sprague Dawley rats by administrating 10 mg of 7,12-dimethylbenz[a]anthracene (DMBA). When a rat developed a palpable mammary tumor, it was either socially isolated (SI) by housing a rat singly or it remained group-housed (GH). Tamoxifen (TAM) or TAM + Jaeumganghwa-tang (JGT) treatment started when the first mammary tumor per rat reached a size of ~11 mm in diameter. TAM was provided at the concentration of 340 ppm via AIN93G diet and JGT at the dose of 500 mg/kg via drinking water. The tumor responses were assessed and TAM treatment was stopped when a rat had exhibited a sustained complete or partial response for nine weeks. Tumor recurrences after TAM therapy were monitored during up to nine additional weeks