Origins and actions of tumor necrosis factor α in postmenopausal breast cancer

Tumor necrosis factor alpha (TNFalpha) has many roles in both physiological and pathological states. Initially thought to cause necrosis of tumors, research has shown that in many tumor types, including breast cancer, TNFalpha contributes to growth and proliferation. The presence of TNFalpha-derived from the tumor and infiltrating immune cells-within a breast tumor microenvironment has been correlated with a more aggressive phenotype, and the postmenopausal ER+ subtype of breast cancers appears to strongly respond to its many pro-growth signaling functions. We discuss how TNFalpha regulates estrogen biosynthesis within the breast, affecting the activity of the key estrogen-synthesizing enzymes aromatase, estrone sulfatase, and 17beta-HSD type 1. Additionally, we describe the anti-adipogenic actions of TNFalpha that are critical in preventing adjacent estrogen-producing adipose fibroblasts from differentiating, ensuring that the tumor maintains a constant source of estrogen-producing cells. We examine how the increased risk of developing breast cancer in older and obese individuals may be linked to the levels of TNFalpha in the body. Finally, we evaluate the feasibility of targeting TNFalpha and its associated pathways as a novel approach to breast cancer therapeutics.