JMJD6 shapes a pro-tumor microenvironment via ANXA1-dependent macrophage polarization in breast cancer.
Bianca CioniSilvia RattiAnnamaria PivaIrene TripodiMatteo MilaniFrancesca MenichettiTiziana LangellaLaura BottiLoris De CeccoClaudia ChiodoniDaniele LecisMario Paolo ColomboPublished in: Molecular cancer research : MCR (2023)
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.
Keyphrases
- estrogen receptor
- single cell
- cell therapy
- induced apoptosis
- poor prognosis
- gene expression
- nitric oxide
- stem cells
- dna methylation
- papillary thyroid
- clinical trial
- signaling pathway
- genome wide
- polycystic ovary syndrome
- breast cancer risk
- fatty acid
- high throughput
- pregnant women
- pregnancy outcomes
- cell cycle arrest
- amino acid
- anti inflammatory
- copy number
- skeletal muscle
- adipose tissue
- cell proliferation
- squamous cell
- binding protein