Medizinische Universität Graz Austria/Österreich - Forschungsportal - Medical University of Graz
Gewählte Publikation:
SHR Neuro Krebs Kardio Lipid Stoffw Microb
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.
RANKL/RANK control Brca1 mutation- .
Cell Res. 2016; 26(7):761-774
Doi: 10.1038/cr.2016.69
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- Co-Autor*innen der Med Uni Graz
- Kenner Lukas
- Popper Helmuth
- Wirnsberger Gerhard
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- 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.
- Find related publications in this database (using NLM MeSH Indexing)
- Animals -
- BRCA1 Protein - genetics
- BRCA2 Protein - genetics
- Breast Neoplasms - drug therapy
- Breast Neoplasms - genetics
- Breast Neoplasms - metabolism
- Breast Neoplasms - pathology
- Cell Proliferation - drug effects
- Cells, Cultured -
- DNA Damage - drug effects
- Epithelial Cells - cytology
- Epithelial Cells - drug effects
- Epithelial Cells - metabolism
- Estrogen Receptor alpha - metabolism
- Female -
- Genotype -
- Humans -
- Mice -
- Mice, Inbred C57BL -
- Mice, Transgenic -
- RANK Ligand - antagonists & inhibitors
- RANK Ligand - genetics
- RANK Ligand - metabolism
- Receptor Activator of Nuclear Factor-kappa B - genetics
- Receptor Activator of Nuclear Factor-kappa B - metabolism
- Receptors, Progesterone - metabolism
- Recombinant Fusion Proteins - pharmacology
- Recombinant Fusion Proteins - therapeutic use
- Stem Cells - cytology
- Stem Cells - metabolism
- Tumor Suppressor Protein p53 - genetics
- Tumor Suppressor Protein p53 - metabolism
- Find related publications in this database (Keywords)
- BRCA1
- RANK
- RANKL
- inherited breast cancer
- mammary progenitor cells