RANKL/RANK control Brca1 mutation-driven mammary tumors

Verena Sigl, Kwadwo Owusu-Boaitey, Purna A Joshi, Anoop Kavirayani, Gerald Wirnsberger, Maria Novatchkova, Ivona Kozieradzki, Daniel Schramek, Nnamdi Edokobi, Jerome Hersl, Aishia Sampson, Ashley Odai-Afotey, Conxi Lazaro, Eva Gonzalez-Suarez, Miguel A Pujana, for CIMBA, Holger Heyn, Enrique Vidal, Jennifer Cruickshank, Hal Berman, Renu Sarao, Melita Ticevic, Iris Uribesalgo, Luigi Tortola, Shuan Rao, Yen Tan, Georg Pfeiler, Eva YHP Lee, Zsuzsanna Bago-Horvath, Lukas Kenner, Helmuth Popper, Christian Singer, Rama Khokha, Laundette P Jones, Josef M Penninger

Breast cancer is the most common female cancer, affecting approximately one in eight women during their life-time. Besides environmental triggers and hormones, inherited mutations in the breast cancer 1 (BRCA1) or BRCA2 genes markedly increase the risk for the development of breast cancer. Here, using two different mouse models, we show that genetic inactivation of the key osteoclast differentiation factor RANK in the mammary epithelium markedly delayed onset, reduced incidence, and attenuated progression of Brca1;p53 mutation-driven mammary cancer. Long-term pharmacological inhibition of the RANK ligand RANKL in mice abolished the occurrence of Brca1 mutation-driven pre-neoplastic lesions. Mechanistically, genetic inactivation of Rank or RANKL/RANK blockade impaired proliferation and expansion of both murine Brca1;p53 mutant mammary stem cells and mammary progenitors from human BRCA1 mutation carriers. In addition, genome variations within the RANK locus were significantly associated with risk of developing breast cancer in women with BRCA1 mutations. Thus, RANKL/RANK control progenitor cell expansion and tumorigenesis in inherited breast cancer. These results present a viable strategy for the possible prevention of breast cancer in BRCA1 mutant patients.Cell Research advance online publication 31 May 2016; doi:10.1038/cr.2016.69.