Abstract This study aims to investigate the impact of the gut microbiome as a host-intrinsic factor in breast cancer metastasis to the lungs. The 5-year survival rate of metastatic breast cancer is 31%, however little is known as to what places patients at risk for metastatic disease. Here, we provide evidence that gut commensal dysbiosis, an inflamed and unbalanced microbiome, modifies the lung tissue microenvironment to promote the growth of hormone receptor-positive (HR+) breast tumor cells in a mast cell-dependent mechanism. This work uses a published model of dysbiosis, where we treat mice with oral broad-spectrum antibiotics for 2 weeks, before allowing 4 days of rest to promote optimal growth of antibiotic-resistant species. Non-dysbiotic controls were given vehicle treatment. The HR+ breast tumor cells PyMT were then administered intravenously (IV) to female C57BL/6 mice, mimicking circulating tumor cells to evaluate metastatic growth within the lungs. Mice with pre-established dysbiosis had significantly enhanced lung tumor burden and reduced survival. Pathology score of the lungs of mice challenged with IV tumors showed that at the same time-point dysbiotic mice display elevated tumor grade and inflammation. Furthermore, Luminex screen showed that the lungs of non-tumor-bearing mice displayed significantly elevated IL-6, a pleiotropic cytokine that has been shown to enhance tumor growth in the lungs. Single-cell RNA sequencing identified that mast cells are the main contributor of IL-6 to the lung environment of dysbiotic mice. Finally, to investigate the role of mast cells in promoting the vulnerability of dysbiotic mice to metastatic growth in the lungs, we treated dysbiotic mice with ketotifen, a mast cell stabilizer, before challenging them with PyMT cells as before. Kaplan-Meier analysis showed that dysbiotic mice treated with ketotifen had significantly improved survival compared to vehicle-treated controls. These findings highlight the significant and under-explored connection between the gut microbiome, the immune system, and tumor metastasis, and provoke future questions to investigate the impact of gut microbiome health as a host-intrinsic factor in breast cancer outcomes. Citation Format: Mika Poblete, Audrey Putelo, Simona Bajgai, Cara Hatzinger, Akshita Mirani, Mirna Perusina Lanfranca, Alkaid Feng, Una Miagkov, Melanie Rutkowski, . Gut commensal dysbiosis modulates the lung microenvironment to promote breast tumor metastasis in a mast cell dependent axis abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 6789.
Poblete et al. (Fri,) studied this question.