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.尽管社交孤立（social isolation）的成因复杂多样，但其最普遍且影响深远的后果之一便是癌症死亡率升高。本研究以斯普拉格-道利大鼠（Sprague Dawley rats）作为临床前模型（preclinical model），发现社交孤立会提升抗雌激素治疗完成后乳腺肿瘤复发的风险。该复发风险升高与乳腺组织及肿瘤中IL6/JAK/STAT3信号通路的上调、线粒体氧化磷酸化（mitochondrial oxidative phosphorylation, OXPHOS）通路的抑制相关。同时受抑制的还有参与线粒体丙酮酸转运及丙酮酸转化为乙酰辅酶A的基因，但乳酸水平未发生明显改变。此外，社交孤立会升高晚期糖基化终末产物受体（receptor for advanced glycation end-products, RAGE）的表达，这与社交孤立相关的胰岛素敏感性受损及体重增加现象相符。上述所有变化均与衰老过程密切相关。在社交孤立的动物中，服用抗炎12味草药复方加味姜活汤（Jaeumganghwa-tang, JGT）可抑制IL6/JAK/STAT3信号通路、上调线粒体氧化磷酸化信号、抑制晚期糖基化终末产物配体S100a8与S100a9的表达，并阻断乳腺肿瘤复发风险的升高。综上，针对社交孤立的癌症幸存者，若聚焦于内分泌治疗完成后的阶段，采用抑制IL6/JAK/STAT3炎性细胞因子信号通路并逆转紊乱的线粒体氧化磷酸化的干预手段，或可最为有效地降低其乳腺癌相关死亡率。