Alterations in the mammary gland and tumor microenvironment of formerly obese mice.

BACKGROUND: Obesity is a risk factor for breast cancer, and women with obesity that develop breast cancer have a worsened prognosis. Within the mammary gland, obesity causes chronic, macrophage-driven inflammation and adipose tissue fibrosis. Weight loss is a recommended intervention to resolve obesity, but the impact of weight loss on the mammary gland microenvironment and in tumors has not been well identified. METHODS: To examine the effects of weight loss following obesity, mice were fed a high-fat diet for 16 weeks to induce obesity, then switched to a low-fat diet for 6 weeks. We examined changes in immune cells, including fibrocytes, which are myeloid lineage cells that have attributes of both macrophages and myofibroblasts, and collagen deposition within the mammary glands of non-tumor-bearing mice and within the tumors of mice that were transplanted with estrogen receptor alpha positive TC2 tumor cells. RESULTS: In formerly obese mice, we observed reduced numbers of crown-like structures and fibrocytes in mammary glands, while collagen deposition was not resolved with weight loss. Following transplant of TC2 tumor cells into the mammary glands of lean, obese, and formerly obese mice, diminished collagen deposition and cancer-associated fibroblasts were observed in tumors from formerly obese mice compared to obese mice. Within tumors of obese mice, increased myeloid-derived suppressor cells and diminished CD8+ T cells were identified, while the microenvironment of tumors of formerly obese mice were more similar to tumors from lean mice. When TC2 tumor cells were mixed with CD11b+CD34+ myeloid progenitor cells, which are the cells of origin for fibrocytes, and transplanted into mammary glands of lean and obese mice, collagen deposition within the tumors of both lean and obese was significantly greater than when tumor cells were mixed with CD11b+CD34- monocytes or total CD45+ immune cells. CONCLUSIONS: Overall, these studies demonstrate that weight loss resolved some of the microenvironmental conditions within the mammary gland that may contribute to tumor progression. Additionally, fibrocytes may contribute to early collagen deposition in mammary tumors of obese mice leading to the growth of desmoplastic tumors.

Alterations in the Mammary Gland and Tumor Microenvironment of Formerly Obese Mice.

Obesity is a risk factor for breast cancer, and women with obesity that develop breast cancer have a worsened prognosis. Within the mammary gland, obesity causes chronic, macrophage-driven inflammation and adipose tissue fibrosis. To examine the impact of weight loss on the mammary microenvironment, mice were fed high-fat diet to induce obesity, then switched to a low-fat diet. In formerly obese mice, we observed reduced numbers of crown-like structures and fibrocytes in mammary glands, while collagen deposition was not resolved with weight loss. Following transplant of TC2 tumor cells into the mammary glands of lean, obese, and formerly obese mice, diminished collagen deposition and cancer-associated fibroblasts were observed in tumors from formerly obese mice compared to obese mice. When TC2 tumor cells were mixed with CD11b+CD34+ myeloid progenitor cells, collagen deposition within the tumors was significantly greater compared to when tumor cells were mixed with CD11b+CD34- monocytes, suggesting that fibrocytes contribute to early collagen deposition in mammary tumors of obese mice. Overall, these studies show that weight loss resolved some of the microenvironmental conditions within the mammary gland that may contribute to tumor progression.

Breast cancer microenvironment and obesity: challenges for therapy.

Women with obesity who develop breast cancer have a worsened prognosis with diminished survival rates and increased rates of metastasis. Obesity is also associated with decreased breast cancer response to endocrine and chemotherapeutic treatments. Studies utilizing multiple in vivo models of obesity as well as human breast tumors have enhanced our understanding of how obesity alters the breast tumor microenvironment. Changes in the complement and function of adipocytes, adipose-derived stromal cells, immune cells, and endothelial cells and remodeling of the extracellular matrix all contribute to the rapid growth of breast tumors in the context of obesity. Interactions of these cells enhance secretion of cytokines and adipokines as well as local levels of estrogen within the breast tumor microenvironment that promote resistance to multiple therapies. In this review, we will discuss our current understanding of the impact of obesity on the breast tumor microenvironment, how obesity-induced changes in cellular interactions promote resistance to breast cancer treatments, and areas for development of treatment interventions for breast cancer patients with obesity.

Obesity-Activated Lung Stromal Cells Promote Myeloid Lineage Cell Accumulation and Breast Cancer Metastasis.

Obesity is correlated with increased incidence of breast cancer metastasis; however, the mechanisms underlying how obesity promotes metastasis are unclear. In a diet-induced obese mouse model, obesity enhanced lung metastasis in both the presence and absence of primary mammary tumors and increased recruitment of myeloid lineage cells into the lungs. In the absence of tumors, obese mice demonstrated increased numbers of myeloid lineage cells and elevated collagen fibers within the lung stroma, reminiscent of premetastatic niches formed by primary tumors. Lung stromal cells isolated from obese tumor-naïve mice showed increased proliferation, contractility, and expression of extracellular matrix, inflammatory markers and transforming growth factor beta-1 (TGFß1). Conditioned media from lung stromal cells from obese mice promoted myeloid lineage cell migration in vitro in response to colony-stimulating factor 2 (CSF2) expression and enhanced invasion of tumor cells. Together, these results suggest that prior to tumor formation, obesity alters the lung microenvironment, creating niches conducive to metastatic growth.