title: Metformin inhibits RANKL and sensitizes cancer stem cells to denosumab.
abstract: The increased propensity of BRCA1 mutation carriers to develop aggressive breast tumors with stem-like properties begins to be understood in terms of osteoprotegerin (OPG)-unrestricted cross-talk between RANKL-overproducing progesterone-sensor cells and cancer-initiating RANK+responder cells that reside within pre-malignant BRCA1mut/+breast epithelial tissue. We recently proposed that, in the absence of hormone influence, cancer-initiating cells might remain responsive to RANKL stimulation, and hence to the therapeutic effects of the anti-RANKL antibody denosumab because genomic instability induced by BRCA1 haploinsufficiency might suffice to cell-autonomously hyperactivate RANKL gene expression. Here we report that the biguanide metformin prevents BRCA1 haploinsufficiency-driven RANKL gene overexpression, thereby disrupting an auto-regulatory feedback control of RANKL-addicted cancer stem cell-like states within BRCA1mut/-cell populations. Moreover, metformin treatment elicits a synergistic decline in the breast cancer-initiating cell population and its self-renewal capacity in BRCA1-mutated basal-like breast cancer cells with bone metastasis-initiation capacity that exhibit primary resistance to denosumab in mammosphere assays. The specific targeting of RANKL/RANK signaling with denosumab is expected to revolutionize prevention and treatment strategies currently available for BRCA1 mutation carriers. Our findings provide a rationale for new denosumab/metformin combinatorial strategies to clinically manage RANKL-related breast oncogenesis and metastatic progression.
authors.affiliation: a Program Against Cancer Therapeutic Resistance(ProCURE) , Metabolism and Cancer Group, Catalan Institute of Oncology , Girona, Catalonia , Spain.|b Molecular Oncology Group , Girona Biomedical Research Institute (IDIBGI) , Girona , Spain.
authors.forename: Elisabet
authors.initials: E
authors.lastname: Cuyàs
authors.affiliation: c Unit of Clinical Research , Catalan Institute of Oncology , Girona, Catalonia , Spain.
authors.forename: Begoña
authors.initials: B
authors.lastname: Martin-Castillo
authors.affiliation: d Deparment of Medical Oncology , Catalan Institute of Oncology , Girona, Catalonia , Spain.|e Department of Medical Sciences , Medical School, University of Girona , Girona , Spain.
authors.forename: Joaquim
authors.identifier: http://orcid.org/0000-0002-0893-7821
authors.initials: J
authors.lastname: Bosch-Barrera
authors.affiliation: a Program Against Cancer Therapeutic Resistance(ProCURE) , Metabolism and Cancer Group, Catalan Institute of Oncology , Girona, Catalonia , Spain.|b Molecular Oncology Group , Girona Biomedical Research Institute (IDIBGI) , Girona , Spain.
authors.forename: Javier A
authors.initials: JA
authors.lastname: Menendez
mesh_terms: D019313:BRCA1 Protein / Q000378:metabolism; D001940:Breast / Q000473:pathology; D045744:Cell Line, Tumor; D000069448:Denosumab / Q000494:pharmacology* / Q000627:therapeutic use; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D004357:Drug Synergism; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects; D057895:Haploinsufficiency / Q000187:drug effects; D006801:Humans; D008687:Metformin / Q000494:pharmacology* / Q000627:therapeutic use; D008954:Models, Biological; D009369:Neoplasms / Q000188:drug therapy / Q000473:pathology / Q000517:prevention & control; D014411:Neoplastic Stem Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D053245:RANK Ligand / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D019313:BRCA1 Protein; C492913:BRCA1 protein, human; D053245:RANK Ligand; D000069448:Denosumab; D008687:Metformin
keywords: BRCA1; RANK; RANKL; breast cancer; denosumab; metformin