RANKL/RANK control Brca1 mutation-driven mammary tumors

Abstract

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.

DOI: 10.1038/cr.2016.69
0200400201520162017
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@inproceedings{Sigl2016RANKLRANKCB, title={RANKL/RANK control Brca1 mutation-driven mammary tumors}, author={Verena Sigl and Kwadwo Owusu-Boaitey and Purna A Joshi and Anoop Kavirayani and Gerald Wirnsberger and Maria Novatchkova and Ivona Kozieradzki and Daniel Schramek and Nnamdi Edokobi and Jerome Hersl and Aishia Sampson and Ashley Odai-Afotey and Conxi Lazaro and Eva Gonzalez-Suarez and Miguel A Pujana and for CIMBA and Holger Heyn and Enrique Vidal and Jennifer Cruickshank and Hal Berman and Renu Sarao and Melita Ticevic and Iris Uribesalgo and Luigi Tortola and Shuan Rao and Yen Tan and Georg Pfeiler and Eva YHP Lee and Zsuzsanna Bago-Horvath and Lukas Kenner and Helmuth Popper and Christian Singer and Rama Khokha and Laundette P Jones and Josef M Penninger}, booktitle={Cell research}, year={2016} }