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.

Extracellular vesicle-mediated transport: Reprogramming a tumor microenvironment conducive with breast cancer progression and metastasis

“…This induction was suggested to involve chaperoning activity of Hsp90 and be at a post-translational level as the RNA expression levels of tumor susceptibility gene 101 were unaffected by leptin [57] . Evidence continues to implicate EVs role in obesity-related risk for breast cancer and favoring of a more aggressive breast cancer phenotype [ 58 , 59 ]. Breast cancer cells actively take up EVs from breast cancer-associated adipocytes and undergo significant transcriptome alterations [60] .…”

Modeling the Role of Cancer-Associated Fibroblasts in Tumor Cell Invasion

“…Additionally, the cellular composition of the TME varies between tumor locations within the body. Stellate cells—a mesenchymal precursor cell—are found in the liver and pancreas, while adipocytes are critical cell types in the realm of breast cancer [ 35 ].…”

Local Biomarkers Involved in the Interplay between Obesity and Breast Cancer

“…TNF-α also promotes migration in the MDA-MB-231 TNBC cell line through upregulation of matrix metalloproteinase 9 (MMP-9) [ 82 ]. In adipose tissue, TNF-α stimulates aromatase expression, and thereby indirectly contributes to breast cancer progression (see below) [ 4 , 83 ].…”

“…In women, breast cancer is the most common cause of cancer worldwide (excluding non-melanoma skin cancer), with an estimated 2.3 million new cases each year [ 2 ]. Risk factors include unchangeable factors (e.g., female gender, age, and genetic mutations) and modifiable factors, such as alcohol consumptions, reproductive factors, physical inactivity, and obesity [ 3 , 4 ]. Since 1975, the prevalence of obesity (body mass index (BMI) ≥ 30 kg/m 2 ) has nearly tripled worldwide and the rates continue to rise [ 5 ].…”