Speaker: Eva González-Suárez,
Bellvitge Biomedical Research Institute (IDIBELL), Bellvitge (Barcelona), Spain

Organizer: Oncology Programme, IRB Barcelona 
Host: Ángel Nebreda, IRB Barcelona
Date: Thursday, 16 February 2012. 16:00h.
Place: Sala Fèlix Serratosa, Parc Cièntific de Barcelona, Spain

Abstract

The cytokine RANKL and its receptor RANK, key proteins in bone remodeling 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. RANK overexpressing mammary epithelial 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. 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. Anti RANKL treatment also attenuates preneoplastic lesions, tumors and lung metastasis in the spontaneous model of mammary tumorigenesis MMTV-neu mice. In all models the reduction in tumorigenesis upon RANKL inhibition is preceded by a reduction in preneoplasias and correlated with rapid and sustained reductions in hormone-induced mammary epithelial proliferation. Altogether these results demonstrate that RANK pathway promotes mammary tumorigenesis and metastasis in a wider tumor spectrum and beyond its established role in bone metastasis. They 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.