Abstract 107: Identifying the role of fibrocytes in obesity-induced mammary gland fibrosis

Obesity significantly increases breast cancer risk. In addition, obese breast cancer patients have an overall worsened prognosis. The complex relationship between obesity and breast tumor growth and aggressiveness is still being examined. Within breast adipose tissue, obesity causes a state of chronic, macrophage-driven inflammation. Chronic inflammation is associated with increased extracellular matrix (ECM) deposition, however, the underlying mechanisms are not completely understood. In mouse models, increased collagen within the mammary microenvironment is a risk factor for tumor formation, as well as more aggressive tumors. To understand how obesity affects collagen deposition in the mammary gland, we used a diet-induced obesity mouse model. We demonstrated that there was significantly greater collagen deposition around the mammary ducts of high-fat diet (HFD) fed mice compared to control diet (CD) fed mice. To understand how myeloid lineage cells contribute to this fibrosis, CD11b+ cells were sorted from mammary glands of CD- and HFD-fed mice using magnetic beads. When cultured, a population of these sorted CD11b+ cells formed adherent colonies, and colony formation was significantly increased in the CD11b+ cells isolated from HFD-fed mice. When examined further, these colonies expressed myofibroblast markers smooth muscle actin (SMA) and collagen I. These colony-forming CD11b+ cells are consistent with fibrocytes, which have been studied in both chronic inflammatory and fibrotic diseases, but have not been studied in obesity. Fibrocytes are a multipotent, bone-marrow-derived population of cells that originate as myeloid progenitor cells and have characteristics of both macrophages and myofibroblasts. Consistent with an increase in fibrocytes in the mammary gland, myeloid progenitor cells (CD45+CD11b+CD34+) were significantly increased in the bone marrow of HFD-fed mice, indicating an upregulation in the progenitor cell population for both monocytes/macrophages and fibrocytes. To examine differentiation of fibrocytes within the mammary gland, FACS-isolated myeloid progenitor cells from the bone marrow of GFP positive mice were transplanted into the inguinal mammary glands of HFD-fed CCR2 null mice, which have limited movement of myeloid lineage cells out of the bone marrow. Within the mammary glands of these transplanted mice, we observed GFP positive cells that also expressed SMA. Together, our results suggest that chronic inflammation within the obese mammary gland leads to increased fibrocyte numbers, as well as increased collagen deposition around mammary ducts. The effects of obesity on breast tissue fibrosis, as well as the cells responsible for this fibrosis, must be elucidated to better address the risk of breast tumor development in obese women. Citation Format: Genevra M. Kuziel, Lisa M. Arendt. Identifying the role of fibrocytes in obesity-induced mammary gland fibrosis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 107.