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Intervention with Muscadine grape extract and probiotics modulates Western Diet-associated Triple-Negative breast tumor growth and improves prognosis in murine models

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title
Intervention with Muscadine grape extract and probiotics modulates Western Diet-associated Triple-Negative breast tumor growth and improves prognosis in murine models
author
Newman, Tiffany M.
abstract
As the obesity epidemic spreads, so does the prevalence of obesity-associated cancers. Obesity and diet quality contribute to both the risk and prognosis of triple-negative breast cancer (TNBC). TNBC is an aggressive breast cancer subtype most often found in pre-menopausal women. TNBC cells do not express estrogen receptor-α (ER-α) or progesterone receptor (PR) and do not overexpress human epidermal growth factor receptor 2 (HER2) which are commonly targeted on breast cancer tumors, making them difficult to treat. TNBC patients often receive harsh chemotherapeutic regimens as their primary treatment. The high-fat, high-sugar western diet (WD) is associated with increased TNBC risk and poor prognosis. WD-mediated chronic inflammation, gut microbial shifts, and impaired metabolism contribute to this association. We initially examined metabolic effects of WD consumption in a female NHP model and reported that metabolic outcomes of WD consumption were associated with gut microbial composition. The microbially-mediated associations of TNBC risk factors with diet suggests that dietary intervention strategies may be successful additions to TNBC treatment plans. We examined a polyphenol-rich muscadine grape extract (MGE) and probiotic supplements containing Lactobacillus and Bifidobacterium as potential intervention strategies to reduce WD-associated TNBC risk factors, moderate TNBC tumor growth, and improve TNBC prognosis by modulating macrophage-mediated inflammation at the tumor and systemic levels. We report that MGE and probiotic intervention successfully ameliorated risk factors of TNBC in healthy C57Bl/6 mice consuming WD. We determined that intervention was associated with reduced body weight, adiposity, inflammation, and fibrosis. We report that MGE and probiotics administration also significantly impacted gut microbial composition and intestinal parameters associated with inflammation. We administered MGE and probiotics in the 4T1 and C3(1)/TAg TNBC models and determined that combined administration of MGE and probiotics reduced tumor growth rate and proliferation. Administration of these treatments was associated with reduced macrophage-mediated inflammation in tumor and mammary gland tissues in the 4T1 model and reduced tumor and intestinal inflammation in the C3(1)/TAg model. We observed shifts in the gut microbial composition of treated mice that may be responsible for some of the observed changes. Overall, this research suggests that the novel dietary intervention combination of MGE and probiotics could be a valuable tool to reduce TNBC tumor growth and improve patient prognosis and quality of life (related to chronic inflammation).
subject
Bifidobacterium
Gut microbiome
Lactobacillus
Lifestyle modification
Natural Product
Nutraceutical
contributor
Cook, Katherine L (advisor)
Gallagher, Patricia E (committee member)
Shively, Carol (committee member)
Miller, Lance (committee member)
Deep, Gagan (committee member)
date
2023-01-24T09:35:43Z (accessioned)
2024-01-23T09:30:05Z (available)
2023 (issued)
degree
Cancer Biology (discipline)
embargo
2024-01-23 (terms)
identifier
http://hdl.handle.net/10339/101773 (uri)
language
en (iso)
publisher
Wake Forest University
type
Dissertation

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