RANK ligand as a potential target for breast cancer prevention in BRCA1-mutation carriers
Details
Publication Year 2016-06-20, Volume 22, Issue #8, Page 933-9
Journal Title
Nat Med
Publication Type
Journal Article
Abstract
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 cells, and deregulated progesterone signaling has been implicated in BRCA1-associated oncogenesis. Coupled with the findings that tumor necrosis factor superfamily member 11 (TNFSF11; also known as RANKL) is a key paracrine effector of progesterone signaling and that RANKL and its receptor TNFRSF11A (also known as RANK) contribute to mammary tumorigenesis, 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.
Publisher
NPG
WEHI Research Division(s)
Stem Cells And Cancer; Systems Biology And Personalised Medicine; Molecular Genetics Of Cancer; Bioinformatics
PubMed ID
27322743
Publisher's Version
https://doi.org/10.1038/nm.4118
Rights Notice
Refer to copyright notice on published article.


Creation Date: 2016-08-09 12:01:48
Last Modified: 2016-08-10 10:12:05
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