Abstract
Epidemiological studies provide strong evidence that obesity and the associated adipose tissue inflammation are risk factors for breast cancer; however, the molecular mechanisms are poorly understood. We evaluated the effect of a high-fat/high-calorie diet on mammary carcinogenesis in the immunocompetent MMTV-PyMT murine model. Four-week old female mice (20/group) were randomized to receive either a high-fat (HF; 60% kcal as fat) or a low-fat (LF; 16% kcal) diet for eight weeks. Body weights were determined, and tumor volumes measured by ultrasound, each week. At necropsy, the tumors and abdominal visceral fat were weighed and plasma collected. The primary mammary tumors, adjacent mammary fat, and lungs were preserved for histological and immunohistochemical examination and quantification of infiltrating macrophages, crown-like structure (CLS) formation, and microvessel density. The body weight gains, visceral fat weights, the primary mammary tumor growth rates and terminal weights, were all significantly greater in the HF-fed mice. Adipose tissue inflammation in the HF group was indicated by hepatic steatosis, pronounced macrophage infiltration and CLS formation, and elevations in plasma monocyte chemoattractant protein-1 (MCP-1), leptin and proinflammatory cytokine concentrations. HF intake was also associated with higher tumor-associated microvascular density and the proangiogenic factor MCP-1. This study provides preclinical evidence in a spontaneous model of breast cancer that mammary adipose tissue inflammation induced by diet, enhances the recruitment of macrophages and increases tumor vascular density suggesting a role for obesity in creating a microenvironment favorable for angiogenesis in the progression of breast cancer.
Highlights
Epidemiological studies have shown that obesity is a risk factor for breast cancer in postmenopausal women, when the tumors are frequently estrogen receptor (ER)-positive and a major mechanism involves elevated aromatase activity and estrogen production in adipose tissue stromal cells [1,2,3]
The MMTV-polyoma middle T oncoprotein (PyMT) transgenic model of spontaneous mammary cancer was used to examine the interactions between a pre-existing and genetically determined enhanced breast cancer risk, adiposity and the associated adipose tissue inflammation resulting from a high dietary fat intake, and their relationship to angiogenesis
Our study is the first to show that monocyte chemoattractant protein-1 (MCP-1) was increased in visceral adipose, mammary adipose tissue and in the tumors of non-immunodeficient mice fed a high-fat diet, indicating a direct complication of obesity and chronic inflammation associated with breast cancer development and progression
Summary
Epidemiological studies have shown that obesity is a risk factor for breast cancer in postmenopausal women, when the tumors are frequently estrogen receptor (ER)-positive and a major mechanism involves elevated aromatase activity and estrogen production in adipose tissue stromal cells [1,2,3]. Among the contributors to the biochemical and molecular mechanisms are the proinflammatory cytokines such as tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6), and the chemokine monocyte chemoattractant protein-1 (MCP-1) which are produced by the macrophages that infiltrate the adipose tissue, and do so in increased numbers in obesity [9,10], the preadipocytes, and mature adipocytes [11,12]. This inflammation has been characterized by “crown-like structures” (CLS) which are formed by aggregation of the infiltrating macrophages around individual adipocytes with resulting cell necrosis and formation of a syncytium of lipid-containing giant multinucleated cells and were shown to be present in increased numbers in obese mice and humans [13,14]
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