Obesity and Age Elevate Tissue-Resident Microbiota Akkermansia muciniphila to Induce Oxidative Stress and Promote Breast Cancer Risk

Obesity is a modifiable risk factor for postmenopausal breast cancer. As obesity-gut microbiome interactions are well known, obesity might also impact tissue-resident microbiome populations as a mechanism promoting breast cancer. Using non-cancerous breast tissue samples, we demonstrated that obesity and aging interact to shift the tissue-resident microbiome in breast cancer patients. Breast tissue from postmenopausal women with obesity displayed a significantly different α-diversity and β-diversity than pre- and postmenopausal women without obesity. At the species level, breast tissue from postmenopausal women with obesity expressed elevated Akkermansia muciniphila abundance when compared with all other groups. A secondary cohort of non-cancerous breast tissue from reduction mammoplasty patients indicated participant body mass index correlates with breast A. muciniphila abundance. Elevated mammary gland A. muciniphila in female MMTV-PyMT mice fed a high-fat Western diet increased tumorigenesis, tumor multiplicity, and oxidative stress markers, and administration of antioxidant N-acetylcysteine reduced A. muciniphila-induced tumorigenesis and redox perturbations. In an orthotopic progression model, mammary gland A. muciniphila in Western diet-fed mice promoted ER+ tumor growth and lung metastases. Taken together, these results suggest obesity and aging interact to enrich breast A. muciniphila abundance, modifying tissue redox balance as a risk factor for obesity-mediated postmenopausal breast cancer.