RANK ligand mediates hormone induced mammary epithelial proliferation and carcinogenesis
E. Gonzalez Suarez1,2, A. Jacob1, J. Jones1, R. Miller1, M. Roudier1, R. Erwert1, J. Pinkas1,3, D. Branstetter1 & W. Dougall1
RANK and RANKL are essential for mammary gland development in mice. We demonstrated that RANK signalling promotes proliferation and impairs mammary epithelial differentiation in mice. RANK and RANKL expression is detected in breast cancer cells. MMTV-RANK acini show hallmarks of transformation in a RANKL dependent manner. After multiple pregnancies MMTV-RANK females spontaneously develop adenocarcinomas, and after DMBA (dimethylbenz(a)anthracene) and MPA (medroxiprogesterone) treatments show a shorter latency and a higher incidence of preneoplastic lesions and adenocarcinomas as compared to wild-type (WT) mice. Reciprocally, selective pharmacologic inhibition of RANKL after progesterone and carcinogen treatment attenuates mammary tumor formation in MMTV-RANK mice and prevents mammary tumor formation in WT mice. Anti RANKL treatment also decreases tumor formation and lung metastasis in MMTV-neu mice. The reduction in tumorigenesis upon RANKL inhibition was preceded by a reduction in preneoplasias and correlated with rapid and sustained reductions in hormone induced mammary epithelial proliferation. These results show that increased RANKL signalling promotes breast cancer initiation in mice and that RANKL is the main mediator of the protumorigenic effects of progesterone. Importantly, these results suggest that increased RANKL signaling may be a risk factor for mammary tumor development and that RANKL inhibitors may be effective for breast cancer treatment.
Declaration of interest: The authors declare taht there is a conflict of interest.
Funding: This research did not receive any specific grant from any funding agency in the public, commercial or not-for-profit sector.