Social Isolation Activates Dormant Mammary Tumors, and Modifies Inflammatory and Mitochondrial Metabolic Pathways in the Rat Mammary Gland

Author:

Andrade Fabia de Oliveira12ORCID,Jin Lu12,Clarke Robert12ORCID,Wood Imani1,Dutton MaryAnn3,Anjorin Chezaray1,Rubin Grace1,Gao Audrey2,Sengupta Surojeet12,FitzGerald Kevin14,Hilakivi-Clarke Leena12

Affiliation:

1. Department of Oncology, Georgetown University, Washington, DC 20057, USA

2. Hormel Institute, University of Minnesota, 801 16th Ave NE, Austin, MN 55912, USA

3. Department of Psychiatry, Georgetown University, Washington, DC 20057, USA

4. Department of Medical Humanities, Creighton University, Omaha, NE 68178, USA

Abstract

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.

Funder

the Ministry of Health & Welfare (MOHW), Republic of Korea

Comprehensive and Integrative Medicine Institute

Georgetown University Dean for Research Pilot grant

Cancer Center Support grant

Publisher

MDPI AG

Subject

General Medicine

Cited by 1 articles. 订阅此论文施引文献 订阅此论文施引文献,注册后可以免费订阅5篇论文的施引文献,订阅后可以查看论文全部施引文献

1. Social Isolation and Breast Cancer;Endocrinology;2023-08-17

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