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Type of publication: Journal Article
Type of document: Full Paper

Year: 2016

Authors: Sigl, V; Owusu-Boaitey, K; Joshi, PA; Kavirayani, A; Wirnsberger, G; Novatchkova, M; Kozieradzki, I; Schramek, D; Edokobi, N; Hersl, J; Sampson, A; Odai-Afotey, A; Lazaro, C; Gonzalez-Suarez, E; Pujana, MA; Cimba, F; Heyn, H; Vidal, E; Cruickshank, J; Berman, H; Sarao, R; Ticevic, M; Uribesalgo, I; Tortola, L; Rao, S; Tan, Y; Pfeiler, G; Lee, EY; Bago-Horvath, Z; Kenner, L; Popper, H; Singer, C; Khokha, R; Jones, LP; Penninger, JM

Title: RANKL/RANK control Brca1 mutation-driven mammary tumors.

Source: Cell Res. 2016; 26(7):761-774

Authors Vetmeduni Vienna:

Kenner Lukas

Vetmed Research Units
Institute of Pathology, Pathology of Laboratory Animals

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.

Keywords Pubmed: Animals
BRCA1 Proteingenetics
BRCA2 Proteingenetics
Breast Neoplasmsdrug therapygeneticsmetabolismpathology
Cell Proliferationdrug effects
Cells, Cultured
DNA Damagedrug effects
Epithelial Cellscytologydrug effectsmetabolism
Estrogen Receptor alphametabolism
Mice, Inbred C57BL
Mice, Transgenic
RANK Ligandantagonists & inhibitorsgeneticsmetabolism
Receptor Activator of Nuclear Factor-kappa Bgeneticsmetabolism
Receptors, Progesteronemetabolism
Recombinant Fusion Proteinspharmacologytherapeutic use
Stem Cellscytologymetabolism
Tumor Suppressor Protein p53geneticsmetabolism

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