BRCA1 haploinsufficiency cell-autonomously activates RANKL expression and generates denosumab-responsive breast cancerinitiating cells
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Denosumab, a monoclonal antibody to the receptor activator of nuclear factor-κB
ligand (RANKL), might be a novel preventative therapy for BRCA1-mutation carriers
at high risk of developing breast cancer. Beyond its well-recognized bone-targeted
activity impeding osteoclastogenesis, denosumab has been proposed to interfere with
the cross-talk between RANKL-producing sensor cells and cancer-initiating RANK+
responder cells that reside within premalignant tissues of BRCA1-mutation carriers.
We herein tested the alternative but not mutually exclusive hypothesis that BRCA1
deficiency might cell-autonomously activate RANKL expression to generate cellular
states with cancer stem cell (CSC)-like properties. Using isogenic pairs of normallike
human breast epithelial cells in which the inactivation of a single BRCA1 allele
results in genomic instability, we assessed the impact of BRCA1 haploinsufficiency on
the expression status of RANK and RANKL. RANK expression remained unaltered but
RANKL was dramatically up-regulated in BRCA1mut/+ haploinsufficient cells relative to
isogenic BRCA1+/+ parental cells. Neutralizing RANKL with denosumab significantly
abrogated the ability of BRCA1 haploinsufficient cells to survive and proliferate as
floating microtumors or “mammospheres” under non-adherent/non-differentiating
conditions, an accepted surrogate of the relative proportion and survival of CSCs.
Intriguingly, CSC-like states driven by epithelial-to-mesenchymal transition or HER2
overexpression traits responded to some extent to denosumab. We propose that
breast epithelium-specific mono-allelic inactivation of BRCA1 might suffice to cellautonomously
generate RANKL-addicted, denosumab-responsive CSC-like states.
The convergent addiction to a hyperactive RANKL/RANK axis of CSC-like states from genetically diverse breast cancer subtypes might inaugurate a new era of cancer
prevention and treatment based on denosumab as a CSC-targeted agent