Preexisting Commensal Dysbiosis Is a Host-Intrinsic Regulator of Tissue Inflammation and Tumor Cell Dissemination in Hormone Receptor–Positive Breast Cancer

Abstract

It is unknown why some patients with hormone receptorpositive (HR þ ) breast cancer present with more aggressive and invasive disease. Metastatic dissemination occurs early in disease and is facilitated by cross-talk between the tumor and tissue environment, suggesting that undefined host-intrinsic factors enhance early dissemination and the probability of developing metastatic disease. Here, we have identified commensal dysbiosis as a host-intrinsic factor associated with metastatic dissemination. Using a mouse model of HR þ mammary cancer, we demonstrate that a preestablished disruption of commensal homeostasis results in enhanced circulating tumor cells and subsequent dissemination to the tumor-draining lymph nodes and lungs. Commensal dysbiosis promoted early inflammation within the mammary gland that was sustained during HR þ mammary tumor progression. Furthermore, dysbiosis enhanced fibrosis and collagen deposition both systemically and locally within the tumor microenvironment and induced significant myeloid infiltration into the mammary gland and breast tumor. These effects were recapitulated both by directly targeting gut microbes using nonabsorbable antibiotics and by fecal microbiota transplantation of dysbiotic cecal contents, demonstrating the direct impact of gut dysbiosis on mammary tumor dissemination. This study identifies dysbiosis as a preexisting, hostintrinsic regulator of tissue inflammation, myeloid recruitment, fibrosis, and dissemination of tumor cells in HR þ breast cancer.Significance: Identification of commensal dysbiosis as a host-intrinsic factor mediating evolution of metastatic breast cancer allows for development of interventions or diagnostic tools for patients at highest risk for developing metastatic disease.See related commentary by Ingman, p. 3539

tRNA Queuosine Modification Enzyme Modulates the Growth and Microbiome Recruitment to Breast Tumors

“…Therefore, the alteration of TJ proteins and microbiome components in the intestine should enhance bacterial translocation by regulating intestinal bacterial interactions with the mucosal surface, which may support bacterial translocation from the intestine to other locations or tumors. Increased cytokines and chemokines in the plasma of mice injected with WT MCF7 cells also support the idea that inflammation and leaky gut promote bacterial dysbiosis [51] and bacterial translocation.…”

Rumen microbiome structure and metabolites activity in dairy cows with clinical and subclinical mastitis

“…Commensal dysbiosis in mammary gland promoted early in ammation within the udder. Further, intestinal ora dysbiosis induced by fecal bacteria transplantation could also trigger the in ammatory cells dissemination into the udder [44]. Subsequent functional prediction analysis uncovered functional pathways of rumen microbes that changed signi cantly among H, SM and CM cows.…”

The Gut Microbiome: A New Player in Breast Cancer Metastasis

“…While these studies are intriguing, a functional relationship between the gut microbiome and breast cancer has yet to be demonstrated until recently. Buchta Rosean and colleagues now present the first evidence that disturbance in the gut microbiome can promote breast cancer metastasis in a mouse model (4). This research is in its early stages and there is still much to be done.…”