RANK mediates tumor-infiltrating regulatory T-cells stimulation of mammary cancer metastasis

Receptor activator of nuclear factor-kB (RANK)-ligand (RANKL) signaling is associated with osteoclast differentiation and bone resorption. Inhibition of this pathway by specific RANKL antibodies is an effective way to reduce bone metastases. Recent studies showed that this pathway was activated in prostate or breast cancer, although its precise mechanism is unknown. The objective of this study [1] was to investigate the source and the role of RANKL and the RANK-RANKL signaling in breast cancer pulmonary metastasis.

Indeed, exogenous RANKL (RANK ligand) in mammary carcinoma cells activates pulmonary metastasis. On the contrary, the silencing of RANK (RANKL receptor) reduces pulmonary metastasis. This prometastatic effect is mediated by reduced expression of metastasis inhibitor factor MASPIN, a protease inhibitor also known as SerpinB5, in breast carcinoma cancer cells. Metastatic spread of carcinoma cells also required CD4+ CD25+ regulatory T cells, in mouse and human breast cancers. These cells are the main producers of RANKL in breast tumors.

These results are consistent with the adverse impact of tumor-infiltrating regulatory T cells on human breast cancer prognosis and suggest that the targeting of RANKL–RANK can be used in conjunction with the therapeutic elimination of primary breast tumors to prevent recurrent metastatic disease.

1. Tan et al. Nature. 2011;470:548-553.