The Tumor Promotional Role of Adipocytes in the Breast Cancer Microenvironment and Macroenvironment

Abstract

The role of the adipocyte in the tumor microenvironment has received significant attention as a critical mediator of the obesity-cancer relationship. Current estimates indicate that 650 million adults have obesity, and thirteen cancers, including breast cancer, are estimated to be associated with obesity. Even in people with a normal body mass index, adipocytes are key players in breast cancer progression because of the proximity of tumors to mammary adipose tissue. Outside the breast microenvironment, adipocytes influence metabolic and immune function and produce numerous signaling molecules, all of which affect breast cancer development and progression. The current epidemiologic data linking obesity, and importantly adipose tissue, to breast cancer risk and prognosis, focusing on metabolic health, weight gain, and adipose distribution as underlying drivers of obesity-associated breast cancer is presented here. Bioactive factors produced by adipocytes, both normal and cancer associated, such as cytokines, growth factors, and metabolites, and the potential mechanisms through which adipocytes influence different breast cancer subtypes are highlighted.

Figure 1

Factors beyond body mass index that predict breast cancer risk. Epidemiologic studies suggest that metabolic health (A), adult weight gain (B), and adipose tissue distribution (C) may drive obesity-associated breast cancer. Mechanisms include increased nutrients (glucose, lipids that traffic among liver, adipocytes, pancreas, and muscle), elevated insulin levels, growth factor production, and inflammation.

Figure 2

Adipocytes near a breast tumor participate in complex communication. The invasive fronts of breast tumors are surrounded by adipocytes that become smaller the closer they are to cancer cells. They transfer lipids, cytokines [eg, interleukin (IL) 6 and IL-8], and growth factors [eg. fibroblast growth factor (FGF), insulin-like growth factor (IGF), and vascular endothelial growth factor (VEGF)] to the environment and cancer cells, which promote breast cancer proliferation, invasion, and facilitate angiogenesis. Both adipocytes and cancer cells recruit immune cells, which facilitate tumor progression.