RANKLed About Breast Cancer

Science Signaling  09 Nov 2010:
Vol. 3, Issue 147, pp. ec341
DOI: 10.1126/scisignal.3147ec341

Two independent groups, Schramek et al. and Gonzalez-Suarez et al., provide evidence implicating RANKL [receptor-activator of NF-κB (RANK) ligand] in progestin-driven breast cancer. Progestins, progesterone derivatives used in both hormone replacement therapies and contraceptives, have been implicated in the development of breast cancers. RANKL, known for its role as an osteoclast differentiation factor, has been implicated in mammary epithelial cell proliferation during pregnancy and has been identified in breast cancer cells. Both groups showed that in vivo exposure to the progestin medroxyprogesterone acetate (MPA) increased the RANKL mRNA and protein content of mouse mammary epithelia and used genetic approaches to investigate its role in breast cancer. Schramek et al. showed that female mice lacking mammary epithelial cell RANK (RANKΔmam mice) exhibited decreased MPA-dependent mammary epithelial cell proliferation compared with control mice and delayed onset of mammary cancer in response to the combination of MPA and the DNA-damaging agent DMBA (7,12-dimethylbenzanthracene). In mammary epithelial cells, RANKL-RANK signals through IκB kinase-α (IKK-α) to NF-κB to cyclin D1, and, consistent with activation of this pathway, MPA promoted nuclear accumulation of phosphorylated IκBα and increased cyclin D1 abundance. In vivo, MPA protected against γ-irradiation–induced mammary epithelial cell apoptosis, an effect that was attenuated in RANKΔmam and IKKαΔmam mice. In a complementary study, Gonzalez-Suarez et al. found that mice overexpressing RANK under the control of the mouse mammary tumor virus (MMTV) promoter (MMTV-RANK mice) showed increased susceptibility to mammary tumors compared with wild-type mice after multiple births or in response to treatment with MPA and DMBA. Conversely, the RANKL inhibitor RANK-Fc inhibited mammary tumor formation in both wild-type and MMTV-RANK mice treated with MPA and DMBA. Indeed, RANK-Fc inhibited mammary tumor formation, preneoplastic lesions, and lung metastases in MMTV-neu mice, which develop spontaneous mammary tumors in the absence of exogenous hormones. Thus, progestins appear to act through RANKL to promote mammary tumor formation, and RANKL inhibition may present a previously unexplored approach to the prevention—and perhaps the treatment—of breast cancer.

D. Schramek, A. Leibbrandt, V. Sigl, L. Kenner, J. A. Pospisilik, H. J. Lee, R. Hanada, P. A. Joshi, A. Aliprantis, L. Glimcher, M. Pasparakis, R. Khokha, C. J. Ormandy, M. Widschwendter, G. Schett, J. M. Penninger, Osteoclast differentiation factor RANKL controls development of progestin-driven mammary cancer. Nature 468, 98–102 (2010). [PubMed]

E. Gonzalez-Suarez, A. P. Jacob, J. Jones, R. Miller, M. P. Roudier-Meyer, R. Erwert, J. Pinkas, D. Branstetter, W. C. Dougall, RANK ligand mediates progestin-induced mammary epithelial proliferation and carcinogenesis. Nature 468, 103–107 (2010). [PubMed]