BRCA1 haploinsufficiency cell-autonomously activates RANKL expression and generates denosumab-responsive breast cancer-initiating cells
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Elisabet Cuyàs1,2, Bruna Corominas-Faja1,2, María Muñoz-San Martín3, Begoña Martin-Castillo2,4, Ruth Lupu5,6, Joan Brunet7,8, Joaquim Bosch-Barrera7,8 and Javier A. Menendez1,2
1Program Against Cancer Therapeutic Resistance (ProCURE), Metabolism and Cancer Group, Catalan Institute of Oncology, Girona, Catalonia, Spain
2Molecular Oncology Group, Girona Biomedical Research Institute (IDIBGI), Girona, Catalonia, Spain
3Neuroimmunology and Multiple Sclerosis Unit, Dr. Josep Trueta University Hospital, Girona Biomedical Research Institute (IDIBGI), Girona, Catalonia, Spain
4Unit of Clinical Research, Catalan Institute of Oncology, Girona, Catalonia, Spain
5Mayo Clinic, Department of Laboratory Medicine and Pathology, Division of Experimental Pathology, Rochester, MN, USA
6Mayo Clinic Cancer Center, Rochester, MN, USA
7Deparment of Medical Oncology, Catalan Institute of Oncology, Girona, Catalonia, Spain
8Department of Medical Sciences, Medical School, University of Girona, Girona, Catalonia, Spain
Keywords: denosumab, RANK, RANKL, cancer stem cells, BRCA1
Received: September 26, 2016 Accepted: February 27, 2017 Published: March 25, 2017
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 normal-like 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 cell-autonomously 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.
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