Exploring the effect of vitamin D on the inflammatory microenvironment of breast tumor in the context of obesity using an in vitro 3D triculture model.

Obesity is a recognized risk factor for breast cancer, the leading cause of cancer death worldwide. Vitamin D (vit D), a molecule with anti-inflammatory effects, can act on different cell types through the presence of its VDR receptor. Our aim was therefore to study the impact of vit D in a 3D co-culture model between PreAd (spheroids of pre-adipocytes from obese women) or Mat-Ad (spheroids of mature adipocytes from obese women), M1-like pro-inflammatory macrophages and mammary cancer spheroids, to mimic the inflammatory breast tumor microenvironment (TME) of a person with obesity. The results showed a decrease in the expression of adipocyte differentiation genes in PreAd, inflammatory cytokines genes in inflammatory macrophages and tumor proliferation genes in cancer spheroids in the coculture system with PreAd, M1-macrophages and cancer cells. In addition, there was a decrease in the secretion of certain key inflammatory cytokines involved in obesity thus decreasing the overall inflammation of the microenvironment. These results were not observed in the coculture with Mat-Ad, M1-macrophages and cancer cells, with little to no effect of vit D on gene expression and an increase of the secretion of key inflammatory cytokines involved in obesity in the microenvironment thus favoring inflammatory microenvironment. These results suggest that, at a physiological concentration, vit D has therefore a more pronounced action on PreAd. Our findings suggest that the effects of vit D on TME depend on adipocyte differentiation, with potential benefits in preadipocytes rich microenvironment but limited efficacy in mature adipocytes rich microenvironment. Further studies are needed to determine the therapeutic relevance of vit D supplementation.