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OBESITY, THE MICROBIOME, AND BREAST CANCER RISK

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title
OBESITY, THE MICROBIOME, AND BREAST CANCER RISK
author
Gaber, Mohamed
abstract
Obesity is a global public health crisis that is no longer exclusive to high-income countries. Unfortunately, obesity is associated with multiple chronic diseases including breast cancer. Mechanisms by which obesity causes breast cancer initiation are not well-understood. Pathophysiologic perturbations caused by obesity may contribute to the breast cancer risk. These include adipokine imbalance (decreased adiponectin and increased leptin), inflammation, immune dysfunction, disruption of insulin/insulin-like growth factor (IGF) signaling, increased local and systemic estrogen levels, and alterations of the microbiome. Premalignant changes such as DNA damage and chronic inflammation were investigated in the context of obesity. We show that obesity-associated factors such as leptin and IGF-1 are capable of inducing DNA damage in non-neoplastic breast epithelial cells. BMI and circulating leptin concentrations in human subjects showed significant associations with DNA damage and oxidative stress. Moreover, African genetic ancestry showed an association with increased levels of DNA damage which could be attributed to their higher IGF-1 levels than the non-Hispanic White subjects. In a cohort of elderly postmenopausal women, we show that obesity causes pro-inflammatory changes in their gut microbiome characterized by the expansion of Proteobacteria. The majority of bacteria in this phylum are flagellated and harbor immunogenic forms of lipopolysaccharide (LPS). In addition, we show in human samples and murine studies that obesity causes elevated systemic and breast tissue levels of the microbial-associated molecular patterns (MAMPs); LPS and flagellin. In vitro and in vivo experiments demonstrate that these MAMPs are contributing to the DNA damage observed in the breast tissues of obese subjects. Moreover, the immunogenicity of LPS determines its genotoxic potential irrespective of the obesity status. Taken together, obesity may induce breast tissue pre-malignant changes such as DNA damage via multitude of factors which include leptin, IGF-1, LPS and flagellin.
subject
Breast cancer
Breast microbiome
DNA damage
Gut microbiome
Lipopolysaccharide (LPS)
Obesity
contributor
Cook, Katherine L. (advisor)
Furdui, Cristina M. (committee member)
Miller, Lance D. (committee member)
Nikiforov, Mikhail A. (committee member)
Soto-Pantoja, David R. (committee member)
date
2024-05-23T08:36:27Z (accessioned)
2024 (issued)
degree
Cancer Biology (discipline)
embargo
2026-05-22 (terms)
2026-05-22 (liftdate)
identifier
http://hdl.handle.net/10339/109458 (uri)
language
en (iso)
publisher
Wake Forest University
type
Dissertation

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