RANK protein and its ligand RANKL (the molecule that allows the protein to perform its function) are involved in the formation of breast tumors, according to a study published this week in Nature. The work has been performed by Eva Gonzalez, currently researcher at the Epigenetics and Cancer Biology Program of Bellvitge Biomedical Research Institute (IDIBELL), along with researchers from the biotechnology company Amgen of Seattle, WA, USA.
RANK and RANKL are key proteins in bone remodelling. Multiple clinical and preclinical studies demonstrate that RANKL inhibition is effective for the treatment of bone related lesions including osteoporosis and bone metastasis.
Amgen Inc, the biotech company where these studies were conducted under Dr Dougall´s supervision, has developed an antibody against RANKL, denosumab, which has proved effective in clinical trials for the management of skeletal metastases.
Dr Eva Gonzalez Suarez, co-author of this work together with her colleague, Allison Jacob, comments, “Studies in mice had demonstrated that a strict regulation of RANKL signalling is essential for mammary gland development but there were no evidences of a functional contribution of RANKL to mammary tumourigenesis.
Previous results by Eva Gonzalez-Suarez et al., and other research groups showed that RANK and RANKL are expressed in mammary epithelial cells, and that RANKL activation promotes proliferation and survival of these cells. These results together with the expression of RANK in breast cancer cell lines and the high incidence of bone metastasis in breast cancer patients drove us to the hypothesis that RANKL signalling may be also playing a role on mammary tumourigenesis, says Eva González.
In order to address the relevance of RANKL signalling on the mammary gland a mouse model with high levels of expression RANK in the mammary epithelia was generated. These mice showed an enhanced susceptibility to mammary tumour formation both spontaneously after multiple pregnancies, and after treatment with a mutagen and progesterone, corroborating the hypothesis. Reciprocally, pharmacological inhibition of RANKL attenuated tumour formation in these mice but also in “wild-type” mice with physiological levels of RANK and RANKL. However, in both models mice were treated with high doses of progesterone.
To evaluate the impact of RANKL in the presence of physiological levels of circulating hormones another mouse model was used, bearing a homologous to Her2 human protein that spontaneously develop mammary tumours with a long latency. RANKL inhibition attenuates tumour formation and drastically inhibits metastasis also in this model. Twenty percent of breast cancer patients show high levels of expression of this protein which is itself a therapeutic target. In all models the reduction of tumourigenesis was preceded by a reduction of pretumoral lesions and hormone induced mammary epithelial proliferation, indicating that RANKL is impacting tumour initiation.
Collectively, the results obtained by Dr Eva Gonzalez-Suarez and her co-workers at Amgen, demonstrates that the permissive contribution of progesterone to increased mammary cancer incidence in mice are mediated by RANKL and highlight a potential role of RANKL inhibition not only for the treatment of bone metastasis but also of primary breast cancer.
The research group leaded by Eva Gonzalez Suarez at the PEBC-IDIBELL in Barcelona continues this line of research investigating the molecular mechanisms of RANKL on mammary gland development, tumorigenesis and metastasis, with the aim to elucidate the putative implication of this pathway in breast cancer in humans.
Eva González-Suárez*1, Allison P Jakob*, Jon Jones, Robert Mille, Martine P. Roudier-Meyer, Ryan Erwert, Jan Pinkas, Dan Branstetter, William C. Dougall. RANK ligand mediates progestin-induced mammary epithelial proliferation and carcinogenesis. Nature doi:10.1038/nature09495 [Epub ahead of print]
*Both authors contributed equally to this work
1 IDIBELL researcher