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

UNLABELLED: Obesity is a modifiable risk factor for postmenopausal breast cancer. As obesity-gut microbiome interactions are well known, obesity might also affect tissue-resident microbiome populations as a mechanism promoting breast cancer. Using noncancerous breast tissue samples, we demonstrated that obesity and aging interact to shift the tissue-resident microbiome in patients with breast cancer. Breast tissue from postmenopausal women with obesity displayed significantly different α-diversity and β-diversity compared with 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 noncancerous breast tissue from reduction mammoplasty patients indicated that participant body mass index correlates with breast A. muciniphila abundance. Elevated mammary gland (MG) A. muciniphila in female MMTV-PyMT mice fed a high-fat Western diet increased tumorigenesis, tumor multiplicity, and oxidative stress markers, and the administration of the antioxidant N-acetylcysteine reduced A. muciniphila-induced tumorigenesis and redox perturbations. In an orthotopic progression model, MG A. muciniphila in Western diet-fed mice promoted estrogen receptor-positive tumor growth and lung metastases. Taken together, these results suggest that obesity and aging interact to enrich breast A. muciniphila abundance, modifying tissue redox balance as a risk factor for obesity-mediated postmenopausal breast cancer. SIGNIFICANCE: Obesity and aging alter the breast tissue microbiome, increasing abundance of tissue-resident Akkermansia muciniphila that promotes tumorigenesis and oxidative stress, revealing a microbial mechanism contributing to postmenopausal obesity-associated breast cancer risk.