RANK ligand as a potential target for breast cancer prevention in BRCA1-mutation carriers.
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.
ACRF Stem Cells and Cancer Division, Walter and Eliza Hall Institute of Medical Research (WEHI), Parkville, Victoria, Australia.|Department of Medical Biology, University of Melbourne, Parkville, Victoria, Australia.
Emma
E
Nolan
ACRF Stem Cells and Cancer Division, Walter and Eliza Hall Institute of Medical Research (WEHI), Parkville, Victoria, Australia.|Department of Medical Biology, University of Melbourne, Parkville, Victoria, Australia.
François
F
Vaillant
Department of Pathology, Amgen Inc., Seattle, Washington, USA.
Daniel
D
Branstetter
ACRF Stem Cells and Cancer Division, Walter and Eliza Hall Institute of Medical Research (WEHI), Parkville, Victoria, Australia.|Department of Medical Biology, University of Melbourne, Parkville, Victoria, Australia.
Bhupinder
B
Pal
Department of Medical Biology, University of Melbourne, Parkville, Victoria, Australia.|Bioinformatics Division, Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia.
Göknur
G
Giner
Imaging Laboratory, Systems Biology and Personalized Medicine Division, Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia.
Lachlan
0000-0002-4388-9642
L
Whitehead
ACRF Stem Cells and Cancer Division, Walter and Eliza Hall Institute of Medical Research (WEHI), Parkville, Victoria, Australia.|Familial Cancer Centre, Royal Melbourne Hospital, Parkville, Victoria, Australia.|Department of Medical Oncology, Royal Melbourne Hospital, Parkville, Victoria, Australia.
Sheau W
SW
Lok
The Breast Service, Royal Melbourne Hospital and Royal Women's Hospital, Parkville, Victoria, Australia.|Department of Surgery, University of Melbourne, Parkville, Victoria, Australia.
Gregory B
GB
Mann
Department of Pathology, Amgen Inc., Seattle, Washington, USA.
Kathy
K
Rohrbach
Department of Pathology, Amgen Inc., Seattle, Washington, USA.
Li-Ya
LY
Huang
Department of Pathology, Amgen Inc., Seattle, Washington, USA.
Rosalia
R
Soriano
Bioinformatics Division, Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia.|Department of Mathematics and Statistics, University of Melbourne, Parkville, Victoria, Australia.
Gordon K
0000-0001-9221-2892
GK
Smyth
Therapeutic Innovation Unit, Amgen Inc., Seattle, Washington, USA.
William C
WC
Dougall
ACRF Stem Cells and Cancer Division, Walter and Eliza Hall Institute of Medical Research (WEHI), Parkville, Victoria, Australia.|Department of Medical Biology, University of Melbourne, Parkville, Victoria, Australia.
Jane E
JE
Visvader
ACRF Stem Cells and Cancer Division, Walter and Eliza Hall Institute of Medical Research (WEHI), Parkville, Victoria, Australia.|Familial Cancer Centre, Royal Melbourne Hospital, Parkville, Victoria, Australia.|Department of Medical Oncology, Royal Melbourne Hospital, Parkville, Victoria, Australia.|Department of Medicine, University of Melbourne, Parkville, Victoria, Australia.|Familial Cancer Centre, Victorian Comprehensive Cancer Centre, Parkville, Victoria, Australia.
Geoffrey J
0000-0001-9386-2416
GJ
Lindeman
D000818:Animals; D019313:BRCA1 Protein / Q000235:genetics*; D050071:Bone Density Conservation Agents / Q000494:pharmacology* / Q000627:therapeutic use; D001940:Breast / Q000187:drug effects* / Q000378:metabolism; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism / Q000517:prevention & control*; D063646:Carcinogenesis / Q000187:drug effects* / Q000235:genetics; D049109:Cell Proliferation / Q000187:drug effects*; D004260:DNA Repair; D000069448:Denosumab / Q000494:pharmacology* / Q000627:therapeutic use; D004195:Disease Models, Animal; D005260:Female; D005434:Flow Cytometry; D006579:Heterozygote; D006801:Humans; D007150:Immunohistochemistry; D051379:Mice; D058990:Molecular Targeted Therapy; D009154:Mutation; D009368:Neoplasm Transplantation; D009940:Organoids / Q000187:drug effects* / Q000378:metabolism; D010862:Pilocarpine / Q000031:analogs & derivatives; D000072036:Prophylactic Mastectomy; D053245:RANK Ligand / Q000037:antagonists & inhibitors* / Q000378:metabolism; D053246:Receptor Activator of Nuclear Factor-kappa B / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013234:Stem Cells / Q000187:drug effects* / Q000378:metabolism; D025521:Tumor Suppressor Proteins; D023041:Xenograft Model Antitumor Assays
D019313:BRCA1 Protein; C492913:BRCA1 protein, human; D050071:Bone Density Conservation Agents; C000605931:Brca1 protein, mouse; D053245:RANK Ligand; D053246:Receptor Activator of Nuclear Factor-kappa B; C505686:TNFRSF11A protein, human; C505688:TNFSF11 protein, human; D025521:Tumor Suppressor Proteins; D010862:Pilocarpine; D000069448:Denosumab; C029118:pilocarpic acid