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pubmed, article, google, scholar, cancer, cas, breast, brca, nature, mammary, cell, research, carriers, central, australia, analysis, gjl, victoria, cells, rank, brcamutation, stem, parkville, prevention, tumor, rankl, access, nat, res, jev, data, lindeman, smyth, geoffrey, tissue, luminal, med, amgen, medical, melbourne, content, gene, progesterone, progenitors, expression, usa, human, institute, cookies, target,

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nature portfolio permissions reprints privacy policy breast-cancer-susceptibility gene brca1 advertising breast service cell-type-specific genomic instability social media east melbourne basal tumor development progestin-driven mammary cancer nature 465 nature 468 nature 406 nature 439 nature cre-mediated gene deletion brca1-mediated mammary tumorigenesis bcl-2-expressing breast tumors li-ya huang medical research council healthy brca1/2-mutation carriers iss-derived reported results human brca1-mutated basal brca1-related breast cancers pre-neoplastic phase rna-seq read counts cell proliferation pathways mammary epithelial cells springerlink instant access permissions rna-seq data deregulated progesterone signaling mammary progesterone mediators human breast tumors operational infrastructure support familial breast cancer dysregulated gene subnetworks brca2-mutation carriers luminal epithelial progenitors normal tissue samples medical research luminal progenitor cells1 personalized medicine division histologically normal tissue assessing differential expression normal breast tissues brca2 mutation prevalence brca1-deficient mice single stem cell

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• Breast cancer prevention for BRCA1- and BRCA-mutation carriers: is there a role for tamoxifen?
• Choices for cancer prevention for women with a BRCA1 mutation?

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      headline:RANK ligand as a potential target for breast cancer prevention in BRCA1-mutation carriers
      description:A new study by Jane Visvader, Geoff Lindeman and colleagues reports on the potential role of RANK signaling in pre-neoplastic breast tissue from BRCA1-mutation carriers and in a mouse model of Brca1-deficient mammary cancer, suggesting that targeting RANK could be explored as an approach to prevent growth of tumors harboring mutated BRCA1. Individuals who have mutations in the breast-cancer-susceptibility gene BRCA1 (hereafter referred to as BRCA1-mutation carriers) frequently undergo prophylactic mastectomy to minimize their risk of breast cancer. The identification of an effective prevention therapy therefore remains a 'holy grail' for the field. Precancerous BRCA1mut/+ tissue harbors an aberrant population of luminal progenitor cells1, and deregulated progesterone signaling has been implicated in BRCA1-associated oncogenesis2,3,4,5. Coupled with the findings that tumor necrosis factor superfamily member 11 (TNFSF11; also known as RANKL) is a key paracrine effector of progesterone signaling6,7,8,9,10 and that RANKL and its receptor TNFRSF11A (also known as RANK) contribute to mammary tumorigenesis11,12,13, we investigated a role for this pathway in the pre-neoplastic phase of BRCA1-mutation carriers. We identified two subsets of luminal progenitors (RANK+ and RANK−) in histologically normal tissue of BRCA1-mutation carriers and showed that RANK+ cells are highly proliferative, have grossly aberrant DNA repair and bear a molecular signature similar to that of basal-like breast cancer. These data suggest that RANK+ and not RANK− progenitors are a key target population in these women. Inhibition of RANKL signaling by treatment with denosumab in three-dimensional breast organoids derived from pre-neoplastic BRCA1mut/+ tissue attenuated progesterone-induced proliferation. Notably, proliferation was markedly reduced in breast biopsies from BRCA1-mutation carriers who were treated with denosumab. Furthermore, inhibition of RANKL in a Brca1-deficient mouse model substantially curtailed mammary tumorigenesis. Taken together, these findings identify a targetable pathway in a putative cell-of-origin population in BRCA1-mutation carriers and implicate RANKL blockade as a promising strategy in the prevention of breast cancer.
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         Breast cancer
         Cancer prevention
         Mechanisms of disease
         Biomedicine
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         Metabolic Diseases
         Infectious Diseases
         Molecular Medicine
         Neurosciences
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               name:Present addresses: Cynosure Clinical Research LLC, North Bend, Washington, USA (D.B.); Queensland Institute of Medical Research (QIMR) Berghofer Medical Research Institute, Herston, Queensland, Australia (W.C.D.).,
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            address:
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      name:Department of Medical Biology, University of Melbourne, Parkville, Australia
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      name:ACRF Stem Cells and Cancer Division, Walter and Eliza Hall Institute of Medical Research (WEHI), Parkville, Australia
      name:Department of Medical Biology, University of Melbourne, Parkville, Australia
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