Reciprocal interactions between the gut microbiome and mammary tissue microenvironment promote distant regulation of breast tumor metastasis

Abstract Establishing commensal dysbiosis, defined as an inflammatory gut microbiome with low biodiversity, prior to breast tumor initiation enhances early dissemination of hormone-receptor positive (HR+) mammary tumor cells into the circulation, distal lymph nodes, and lungs. Here, we sought to define mammary tissue mediators of dysbiosis-induced tumor dissemination. Commensal dysbiosis increased mast cell numbers in the pre-malignant mammary tissue, with numbers remaining elevated in the presence of a tumor. During early tumor progression, increased mast cell numbers correlated with increased numbers of activated fibroblasts and collagen I protein levels in mammary tissues. Fibroblast activation and tissue remodeling are associated with enhanced breast tumor metastasis. Although mast cell degranulation is known to trigger fibrosis in other disease models, it is unknown whether mammary tissue mast cells influence dissemination of tumor cells. To investigate the role of mast cells during tumor dissemination, mice were treated with mast cell stabilizers ketotifen or cromolyn. Notably, inhibition of mast cell degranulation significantly reduced fibroblast activation and dissemination of tumor cells into the blood of dysbiotic animals. Collagen levels in mammary tissues from women diagnosed with HR+ breast cancer also correlated with mast cell abundance, suggesting mast cell-mediated fibroblast activation is relevant to human disease. Together, these data demonstrate that mast cells recruited into the pre-malignant mammary tissue in response to commensal dysbiosis orchestrate early dissemination of HR+ breast tumors through activation of tissue fibroblasts.