Department of Oncology, Georgetown University, Washington, DC 20057, USA.
Hormel Institute, University of Minnesota, 801 16th Ave NE, Austin, MN 55912, USA.
Cells. 2023 Mar 21;12(6):961. doi: 10.3390/cells12060961.
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.
尽管社交隔离的起源是多因素的，但它对乳腺癌死亡率的影响最大。其发生机制尚不清楚，但许多研究表明，社交隔离会增加循环炎症细胞因子并损害线粒体代谢。我们使用雌激素受体阳性乳腺癌的临床前 Sprague Dawley 大鼠模型，研究了社交隔离是否会损害他莫昔芬治疗的反应并增加肿瘤从休眠中出现的风险，从而增加其复发的风险。我们还研究了社交隔离是否会影响他莫昔芬治疗的大鼠乳腺中的哪些信号通路，以及抗炎草药混合物是否可以阻断社交隔离的影响。社交隔离增加了他莫昔芬治疗后休眠乳腺肿瘤复发的风险。复发风险增加与多种信号通路的变化有关，包括乳腺和肿瘤中 IL6/JAK/STAT3 信号的上调以及线粒体氧化磷酸化（OXPHOS）途径的抑制。此外，社交隔离会增加晚期糖基化终产物受体（RAGE）的表达，这与社交隔离导致的胰岛素敏感性降低和体重增加有关。在社交隔离的动物中，草药产品抑制了 IL6/JAK/STAT3 信号，上调了 OXPHOS 信号，抑制了 RAGE 配体 S100a8 和 S100a9 的表达，并防止了休眠乳腺肿瘤的复发增加。通过在激素治疗完成后使用同时针对多种不同途径（包括炎症和线粒体代谢途径）的干预措施，针对社交隔离幸存者的这一时期，可能最有效地预防社交隔离导致的乳腺癌死亡率增加。
