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Nat Med. 2016 Aug;22(8):933-9. doi: 10.1038/nm.4118. Epub 2016 Jun 20.

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

Author information

1
ACRF Stem Cells and Cancer Division, Walter and Eliza Hall Institute of Medical Research (WEHI), Parkville, Victoria, Australia.
2
Department of Medical Biology, University of Melbourne, Parkville, Victoria, Australia.
3
Department of Pathology, Amgen Inc., Seattle, Washington, USA.
4
Bioinformatics Division, Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia.
5
Imaging Laboratory, Systems Biology and Personalized Medicine Division, Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia.
6
Familial Cancer Centre, Royal Melbourne Hospital, Parkville, Victoria, Australia.
7
Department of Medical Oncology, Royal Melbourne Hospital, Parkville, Victoria, Australia.
8
The Breast Service, Royal Melbourne Hospital and Royal Women's Hospital, Parkville, Victoria, Australia.
9
Department of Surgery, University of Melbourne, Parkville, Victoria, Australia.
10
Department of Mathematics and Statistics, University of Melbourne, Parkville, Victoria, Australia.
11
Therapeutic Innovation Unit, Amgen Inc., Seattle, Washington, USA.
12
Department of Medicine, University of Melbourne, Parkville, Victoria, Australia.
13
Familial Cancer Centre, Victorian Comprehensive Cancer Centre, Parkville, Victoria, Australia.

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 BRCA1(mut/+) 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 BRCA1(mut/+) 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.

Comment in

PMID:
27322743
DOI:
10.1038/nm.4118
[Indexed for MEDLINE]

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