JMJD6 shapes a pro-tumor microenvironment via ANXA1-dependent macrophage polarization in breast cancer.

Breast cancer (BC) is the most common type of cancer in women worldwide, with the luminal subtype being the most widespread. Although characterized by better prognosis compared to other subtypes, luminal BC is still considered a threatening disease due to therapy resistance which occurs via both cell- and non-cell-autonomous mechanisms. Jumonji domain containing 6, arginine demethylase and lysine hydroxylase (JMJD6) is endowed with a negative prognostic value in luminal BC and, via its epigenetic activity, it is known to regulate many intrinsic cancer cell pathways. So far, the effect of JMJD6 in molding the surrounding microenvironment has not been explored. Here, we describe a novel function of JMJD6 showing that its genetic inhibition in BC cells suppresses lipid droplet (LD) formation and ANXA1 expression, via estrogen receptor alpha (ERα) and PPARα modulation. Reduction of intracellular ANXA1 results in decreased release in the tumor microenvironment, ultimately preventing M2-type macrophage polarization and tumor aggressiveness. Implications: Our findings identify JMJD6 as a determinant of BC aggressiveness and provide the rationale for the development of inhibitory molecules to reduce disease progression also through the remodeling of tumor microenvironment composition.