СтатьяПоддержка исследования: вне правительства СШАПоддержка NIH: внешняя программаПоддержка правительства СШАНазвание и аннотация: Перевод в очереди
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Sigl Verena, Owusu-Boaitey Kwadwo, Joshi Purna A, Kavirayani Anoop, Wirnsberger Gerald, Novatchkova Maria, Kozieradzki Ivona, Schramek Daniel, Edokobi Nnamdi, Hersl Jerome, Sampson Aishia, Odai-Afotey Ashley, Lazaro Conxi, Gonzalez-Suarez Eva, Pujana Miguel A, Cimba For, Heyn Holger, Vidal Enrique, Cruickshank Jennifer, Berman Hal, Sarao Renu, Ticevic Melita, Uribesalgo Iris, Tortola Luigi, Rao Shuan, Tan Yen, Pfeiler Georg, Lee Eva Yhp, Bago-Horvath Zsuzsanna, Kenner Lukas, Popper Helmuth, Singer Christian, Khokha Rama, Jones Laundette P, Penninger Josef M
Аннотация
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.