RANKL inhibition: a promising novel strategy for breast cancer treatment.

The cytokine RANKL and its receptor RANK, key proteins in bone remodelling and bone metastasis, are essential for mammary gland development in mice. RANK absence or overexpression results in a lactation defect and a non-functional mammary gland. RANKL signalling mediates progesterone-induced proliferation and expansion of the stem cell compartment in the mouse mammary gland. RANK overexpressing mammary epithelial acini show hallmarks of transformation in a RANKL-dependent manner. Complementary gain- and loss-of-function approaches (RANK transgenic and knock-out mouse models and pharmacological RANKL inhibition) define a direct contribution of this pathway to progestin-driven mammary cancer. Moreover, decreased RANKL signalling attenuates preneoplasic lesions and lung metastasis in the spontaneous model of mammary tumorigenesis MMTV-neu, suggesting that RANK pathway promotes mammary tumorigenesis and metastasis in a wider tumour spectrum and beyond its established role in bone metastasis. In this review, we summarise the role of the RANKL pathway in mammary gland development, breast cancer and metastasis, and discuss the potential application of RANKL inhibition for breast cancer treatment.