Melatonin interferes in the desmoplastic reaction in breast cancer by regulating cytokine production

Melatonin exerts oncostatic effects on breast cancer by interfering with the estrogen signaling pathways. Melatonin inhibits aromatase enzyme in breast cancer cells and fibroblasts. In addition, melatonin stimulates the adipogenic differentiation of fibroblasts. Our objective was to study whether melatonin interferes in the desmoplastic reaction by regulating some factors secreted by malignant cells, tumor necrosis factor (TNF)-a, interleukin (IL)-11, and interleukin (IL)-6. To accomplish this, we co-cultured 3T3-L1 cells with MCF-7 cells. The addition of breast cancer cells to the co-cultures inhibited the differentiation of 3T3-L1 preadipocytes to mature adipocytes, by reducing the intracytoplasmic triglyceride accumulation, an indicator of adipogenic differentiation, and also stimulated their aromatase activity. Melatonin counteracted the inhibitory effect on adipocyte differentiation and aromatase activity induced by MCF-7 cells in 3T3-L1 cells. The levels of cytokines in the co-culture media were 10 times those found in culture of 3T3-L1 cells alone. Melatonin decreased the concentrations of cytokines in the media and counteracted the stimulatory effect induced by MCF-7 cells on the cytokine levels. One millimolar melatonin induced a reduction in TNF-a, IL-6, and IL-11 mRNA expression in MCF-7 and 3T3-L1 cells. The findings suggest that melatonin may play a role in the desmoplastic reaction in breast cancer through a downregulatory action on the expression of antiadipogenic cytokines, which decrease the levels of these cytokines. Lower levels of cytokines stimulate the differentiation of fibroblasts and decrease both aromatase activity and expression, thereby reducing the number of estrogen-producing cells proximal to malignant cells.