RANK ligand as a potential target for breast cancer prevention in BRCA1-mutation carriers

Nolan, E; Vaillant, F; Branstetter, D; Pal, B; Giner, G; Whitehead, L; Lok, SW; Mann, GB; Kathleen Cuningham Foundation Consortium for Research into Familial Breast Cancer,; Rohrbach, K; Huang, LY; Soriano, R; Smyth, GK; Dougall, WC; Visvader, JE; Lindeman, GJ

Author(s): Nolan, E; Vaillant, F; Branstetter, D; Pal, B; Giner, G; Whitehead, L; Lok, SW; Mann, GB; Kathleen Cuningham Foundation Consortium for Research into Familial Breast Cancer,; Rohrbach, K; Huang, LY; Soriano, R; Smyth, GK; Dougall, WC; Visvader, JE; Lindeman, GJ;
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
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
NHMRC Grants: NHMRC/1016701, NHMRC/1040978, NHMRC/1054618, NHMRC/1058892, NHMRC/637307, NHMRC/1078730, NHMRC/1037230,
Terms of Use/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