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Social Isolation Activates Dormant Mammary Tumors, and Modifies Inflammatory and Mitochondrial Metabolic Pathways in the Rat Mammary Gland
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. U...
Autores principales: | , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2023
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10047513/ https://www.ncbi.nlm.nih.gov/pubmed/36980301 http://dx.doi.org/10.3390/cells12060961 |
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author | Andrade, Fabia de Oliveira Jin, Lu Clarke, Robert Wood, Imani Dutton, MaryAnn Anjorin, Chezaray Rubin, Grace Gao, Audrey Sengupta, Surojeet FitzGerald, Kevin Hilakivi-Clarke, Leena |
author_facet | Andrade, Fabia de Oliveira Jin, Lu Clarke, Robert Wood, Imani Dutton, MaryAnn Anjorin, Chezaray Rubin, Grace Gao, Audrey Sengupta, Surojeet FitzGerald, Kevin Hilakivi-Clarke, Leena |
author_sort | Andrade, Fabia de Oliveira |
collection | PubMed |
description | 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. |
format | Online Article Text |
id | pubmed-10047513 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-100475132023-03-29 Social Isolation Activates Dormant Mammary Tumors, and Modifies Inflammatory and Mitochondrial Metabolic Pathways in the Rat Mammary Gland Andrade, Fabia de Oliveira Jin, Lu Clarke, Robert Wood, Imani Dutton, MaryAnn Anjorin, Chezaray Rubin, Grace Gao, Audrey Sengupta, Surojeet FitzGerald, Kevin Hilakivi-Clarke, Leena Cells Article 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. MDPI 2023-03-21 /pmc/articles/PMC10047513/ /pubmed/36980301 http://dx.doi.org/10.3390/cells12060961 Text en © 2023 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Article Andrade, Fabia de Oliveira Jin, Lu Clarke, Robert Wood, Imani Dutton, MaryAnn Anjorin, Chezaray Rubin, Grace Gao, Audrey Sengupta, Surojeet FitzGerald, Kevin Hilakivi-Clarke, Leena Social Isolation Activates Dormant Mammary Tumors, and Modifies Inflammatory and Mitochondrial Metabolic Pathways in the Rat Mammary Gland |
title | Social Isolation Activates Dormant Mammary Tumors, and Modifies Inflammatory and Mitochondrial Metabolic Pathways in the Rat Mammary Gland |
title_full | Social Isolation Activates Dormant Mammary Tumors, and Modifies Inflammatory and Mitochondrial Metabolic Pathways in the Rat Mammary Gland |
title_fullStr | Social Isolation Activates Dormant Mammary Tumors, and Modifies Inflammatory and Mitochondrial Metabolic Pathways in the Rat Mammary Gland |
title_full_unstemmed | Social Isolation Activates Dormant Mammary Tumors, and Modifies Inflammatory and Mitochondrial Metabolic Pathways in the Rat Mammary Gland |
title_short | Social Isolation Activates Dormant Mammary Tumors, and Modifies Inflammatory and Mitochondrial Metabolic Pathways in the Rat Mammary Gland |
title_sort | social isolation activates dormant mammary tumors, and modifies inflammatory and mitochondrial metabolic pathways in the rat mammary gland |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10047513/ https://www.ncbi.nlm.nih.gov/pubmed/36980301 http://dx.doi.org/10.3390/cells12060961 |
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