Estrogens and progesterones are major drivers of breast development but also 
promote carcinogenesis in this organ. Yet, their respective roles and the 
mechanisms underlying their action in the human breast are unclear. Receptor 
activator of nuclear factor κB ligand (RANKL) has been identified as a pivotal 
paracrine mediator of progesterone function in mouse mammary gland development 
and mammary carcinogenesis. Whether the factor has the same role in humans is of 
clinical interest because an inhibitor for RANKL, denosumab, is already used for 
the treatment of bone disease and might benefit breast cancer patients. We show 
that progesterone receptor (PR) signaling failed to induce RANKL in PR(+) breast 
cancer cell lines and in dissociated, cultured breast epithelial cells. In 
clinical specimens from healthy donors and intact breast tissue microstructures, 
hormone response was maintained and RANKL expression was under progesterone 
control, which increased RNA stability. RANKL was sufficient to trigger cell 
proliferation and was required for progesterone-induced proliferation. The 
findings were validated in vivo where RANKL protein expression in the breast 
epithelium correlated with serum progesterone levels and the protein was 
expressed in a subset of luminal cells that express PR. Thus, important hormonal 
control mechanisms are conserved across species, making RANKL a potential target 
in breast cancer treatment and prevention.