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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-κBligand (RANKL), might be a novel preventative therapy for BRCA1-mutation carriersat high risk of developing breast cancer. Beyond its well-recognized bone-targetedactivity impeding osteoclastogenesis, denosumab has been proposed to interfere withthe 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 BRCA1deficiency might cell-autonomously activate RANKL expression to generate cellularstates with cancer stem cell (CSC)-like properties. Using isogenic pairs of normallikehuman breast epithelial cells in which the inactivation of a single BRCA1 alleleresults in genomic instability, we assessed the impact of BRCA1 haploinsufficiency onthe expression status of RANK and RANKL. RANK expression remained unaltered butRANKL was dramatically up-regulated in BRCA1mut/+ haploinsufficient cells relative toisogenic BRCA1+/+ parental cells. Neutralizing RANKL with denosumab significantlyabrogated the ability of BRCA1 haploinsufficient cells to survive and proliferate asfloating microtumors or “mammospheres” under non-adherent/non-differentiatingconditions, an accepted surrogate of the relative proportion and survival of CSCs.Intriguingly, CSC-like states driven by epithelial-to-mesenchymal transition or HER2overexpression traits responded to some extent to denosumab. We propose thatbreast epithelium-specific mono-allelic inactivation of BRCA1 might suffice to cellautonomouslygenerate 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 cancerprevention and treatment based on denosumab as a CSC-targeted agent

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