The gut commensal microbiome remotely regulates mammary tissue mast cells to induce metastatic dissemination of HR+ breast cancer

Metastatic breast cancer is a treatable but uncurable disease. Around 75% of patients with metastatic breast cancer were diagnosed with hormone-receptor positive (HR+) breast tumors, highlighting the need to further define the factors that enable metastatic dissemination of HR+ breast cancer cells. According to the recent epidemiological results, HR+ breast cancer patients experienced heterogeneous outcomes, despite receiving comparable treatments. These data raise the possibility that tumor-independent factors influence metastatic capacity of HR+ tumor cells.

Our recently published study revealed that commensal dysbiosis, defined as an inflammatory gut microbiome with low biodiversity, established prior to breast tumor initiation enhances dissemination of HR+ tumor cells. Our study demonstrated that the gut commensal microbiome is a host-intrinsic factor that influences the metastatic behavior of mammary tumor cells. However, the cellular and molecular mechanisms underlying dysbiosis-induced tumor dissemination remain unknown.

In this dissertation, we sought to identify how cellular changes in mammary tissues that arise in response to gut commensal dysbiosis enhance dissemination of HR+ breast tumor cells. Utilizing multiplex flow cytometry and histological approaches, we determined that gut commensal dysbiosis increases the abundance and profibrogenicity of mast cells in normal mammary tissues. Coupling pharmacological inhibitors and adoptive transfer approaches, we demonstrated that mammary tissue-associated mast cells from non-tumor- bearing dysbiotic mice are sufficient to induce HR+ tumor dissemination. The
collagen levels in adjacent mammary tissues from HR+ breast cancer patients are positively correlated with mast cell density and tumor recurrence, supporting the idea that mast cell-mediated fibrosis in mammary tissues contributes to poor outcomes in HR+ breast cancer patients. This study illuminates how crosstalk occurring between the gut microbiome and mammary tissue lead to preconditioning of tissue-associated mast cells to increase HR+ tumor dissemination. These findings will allow for an in-depth knowledge of the role of commensal microbiome in the early dissemination of HR+ breast tumor cells with the ultimate goal of developing therapeutic strategies to reduce metastasis in HR+ breast cancer patients.