Commensal dysbiosis alters the tumor microenvironment in luminal breast cancer

Abstract

Abstract Many factors, including diet, race, and recurrent use of antibiotics, have been associated with an adverse outcome in breast cancer. These extrinsic factors also significantly impact the composition of commensal microbes. This is relevant, as a recent clinical trial demonstrated that patients with advanced hormone receptor+breast cancer had commensal dysbiosis, or significantly reduced composition of commensal microbes, supporting previous studies demonstrating that commensal microbes influence both the systemic immune environment and breast cancer progression. Dysbiosis was additionally shown to promote liver fibrosis in a mouse model of nonalcoholic fatty liver disease. As collagen deposition in mammary tissue is known to associate with breast cancer aggressiveness and metastasis, we hypothesized that dysbiosis enhances metastatic disease in luminal breast cancer through systemic changes to the immune environment, ultimately altering the extracellular matrix of tumors and mediating metastatic disease. To investigate this, we utilized a transplantable model of luminal HR+breast cancer where tumor fragments are transplanted into recipients with or without established commensal dysbiosis. We demonstrate that although the growth of primary tumors is not affected, commensal dysbiosis increases collagen deposition and macrophage infiltration in transplanted tumor fragments. Systemically, dysbiosis amplifies the production of CCL2, a chemokine associated with macrophage infiltration and metastatic potential. These data suggest that commensal dysbiosis enhances collagen deposition in breast tumors and influences the tumor microenvironment, potentially promoting metastatic disease.