Microbe-associated molecular patterns differentially mediate carcinogenic alterations of the breast tissue in the context of obesity

Sep 22, 2026

Obesity is a modifiable risk factor for breast cancer, but how obesity-driven microbial shifts raise risk remains unclear. This study examines microbial-associated molecular pattern (MAMP) signaling in genome instability and inflammation. Human samples show chronic elevation of lipopolysaccharide (LPS) and flagellin in breast tissue, while lipoteichoic acid (LTA) is not increased. LPS and flagellin trigger DNA damage, oxidative stress, and inflammatory cytokine programs via TLR signaling and NF-κB, including correlations with Proteobacteria abundance.

LanguageEnglish

CategoryResearch & Report

FormatPDF

Pages14

Reading Time35 min

AccessFree to download

Introduction

Obesity as a modifiable risk factor

Microbiome, dysbiosis, and disease links

Metabolic endotoxemia and MAMPs

Neoplasia 73 (2026) 101284 Contents lists available at ScienceDirect Neoplasia journal [homepage:](homepage: www.elsevier.com/locate/neo)[ www.elsevier.com/locate/neo](homepage: www.elsevier.com/locate/neo) | Original Research
Microbe-associated molecular patterns differentially mediate carcinogenic alterations of the breast tissue in the context of obesity | | | | | --- | --- | --- | --- | | Mohamed Gabera, Lauren M. Mouldena , Adam S. Wilson a , Valerie Payne a, Julia Holmes a, Kayla Nearya, Abigail Peoples b, Mary L. Duet b, Adam J. Katz b, Pierre-Alexandre Vidic,* , Katherine L. Cook a,d,e,**
a Department of Cancer Biology, Wake Forest University School of Medicine, Winston-Salem, NC, 27157, USA b Department of Plastic and Reconstructive Surgery, Wake Forest University School of Medicine, Winston-Salem, NC, USAc Institut de Canc´erologie de l’Ouest, Angers, 49055, France
d Department of Surgery, Wake Forest University School of Medicine, Winston-Salem, NC, 27157, USA
e Atrium Health Wake Forest Baptist Comprehensive Cancer Center, Wake Forest University School of Medicine, Winston-Salem, NC, 27157, USA | | | | | A R T I C L E I N F O | | A B S T R A C T | | | Keywords:
Breast Cancer Obesity Microbiome Inflammation Prevention
DNA damage Lipopolysaccharide Flagellin Lipoteichoic Acid Proteobacteria
Reactive Oxygen Species (ROS) | | Obesity is a risk factor for breast cancer. Obesity alters the microbiome and microbiome perturbations are reported in breast cancer patients. Yet, the impact of obesity-mediated microbial shifts on breast cancer risk remains unclear. Here, we investigate the effect of microbial-associated molecular pattern (MAMP) signaling on genome instability and inflammation. We show in human samples that obesity chronically elevates breast tissue levels of two MAMPs: lipopolysaccharide (LPS) and flagellin. In contrast, obesity was not associated with chronic elevations in lipoteichoic acid (LTA). Injections of LPS and flagellin in mouse mammary glands (MG) were sufficient to induce DNA damage and inflammation. Moreover, DNA damage was reduced in MG of animals on a high-fat diet by knockdown of toll-like receptors for LPS and flagellin (TLR4 and TLR5), but not TLR2 (LTA receptor). Experiments with breast acini cultures demonstrated LPS and flagellin (but not LTA) induce DNA double-strand breaks via TLR and reactive oxygen species (ROS) generation. Similarly, LPS and flagellin mediated nuclear factor-kappa B (NF-κB) pathway activation and increased expression of inflammatory cytokines. Analyses of non-cancerous breast tissue microbiome revealed an enrichment of Proteobacteria in obese women. Proteobacteria often contain LPS and many of these bacteria are flagellated. Tissue-resident Proteobacteria abundance correlated with breast tissue DNA damage. Our findings show that LPS and flagellin are systemic and local mediators of obesity-induced microbiome alterations, predisposing the breast to pre-malignant changes. These results underscore the importance of considering the tissue-resident microbiome as a biomarker of risk to improve primary prevention of breast cancer. Significance: Obesity differentially modulates non-cancerous breast tissue microbial-associated molecular pattern signaling, enriching LPS and flagellin, to promote oxidative stress and DNA damage. | | Introduction Obesity is one of the few modifiable risk factors for breast cancer. Several mechanisms have been proposed for the obesity-breast cancer risk connection, including imbalance in adipokine levels, effects of local and systemic inflammation, disruption of insulin and insulin-like growth factor signaling, and increased local and systemic estrogen levels [1,2]. The microbiome has been shown to influence these mechanisms, suggesting a key link between microbiota and obesity-mediated breast cancer risk [3]. The gut microbiome consists of two major phyla, Bacteroidetes and Firmicutes, representing mor

FAQs

How does obesity change breast tissue MAMP levels in the study?

Obesity chronically elevates breast tissue levels of LPS and flagellin. It is not associated with chronic elevations in lipoteichoic acid (LTA).

What effects do LPS and flagellin have on mammary glands in mice?

Injections of LPS and flagellin into mouse mammary glands are sufficient to induce DNA damage and inflammation.

Through which mechanisms do LPS and flagellin drive DNA damage and inflammation?

In breast acini cultures, LPS and flagellin induce DNA double-strand breaks via TLR signaling and reactive oxygen species (ROS) generation, and they activate the NF-κB pathway to increase inflammatory cytokine expression.

Sep 22, 2026

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