Figure 3.

Epithelial-stromal interactions in breast tumors inhibit adipogenic differentiation and enhance estrogen formation by increasing the aromatase activity of the undifferentiated fibroblasts. All these actions are mediated by cytokines, such as TNF-α, IL-6 and IL-11, produced by malignant epithelial cells. Melatonin reduces the formation of undifferentiated fibroblasts surrounding malignant epithelial cells by stimulating the differentiation of fibroblasts to mature adipocytes and adipogenesis, and by decreasing the aromatase activity of the fibroblasts and adipocytes through a downregulatory action on the expression of antiadipogenic cytokines, which decreases the levels of these cytokines. Lower levels of TNF-α, IL-6 and IL-11 stimulate the differentiation of fibroblasts and decrease the aromatase activity and expression. Melatonin also decreases the production of PGE₂ by malignant cells, which upregulates aromatase expression both in the tumor itself and in the surrounding adipose tissue, and enhances the production of IL-11 by tumor cells. Figure modified from Álvarez-García et al (39) and Cos et al (23). TNF-α, tumor necrosis factor-α; IL, interleukin.