Cuyàs Elisabet, Corominas-Faja Bruna, Martín María Muñoz-San, Martin-Castillo Begoña, Lupu Ruth, Brunet Joan, Bosch-Barrera Joaquim, Menendez Javier A
Program Against Cancer Therapeutic Resistance (ProCURE), Metabolism and Cancer Group, Catalan Institute of Oncology, Girona, Catalonia, Spain.
Molecular Oncology Group, Girona Biomedical Research Institute (IDIBGI), Girona, Spain.
Oncotarget. 2017 May 23;8(21):35019-35032. doi: 10.18632/oncotarget.16558.
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.
地诺单抗是一种针对核因子κB受体活化因子配体（RANKL）的单克隆抗体，可能是对有患乳腺癌高风险的BRCA1突变携带者的一种新型预防性疗法。除了其广为人知的阻碍破骨细胞生成的骨靶向活性外，地诺单抗还被认为可干扰RANKL产生传感细胞与BRCA1突变携带者癌前组织中存在的致癌RANK +反应细胞之间的相互作用。我们在此测试了另一种但并非相互排斥的假设，即BRCA1缺陷可能会自主激活RANKL表达，从而产生具有癌症干细胞（CSC）样特性的细胞状态。使用单BRCA1等位基因失活导致基因组不稳定的同基因正常样人乳腺上皮细胞对，我们评估了BRCA1单倍体不足对RANK和RANKL表达状态的影响。相对于同基因BRCA1 + / +亲代细胞，BRCA1mut / +单倍体不足细胞中的RANK表达保持不变，但RANKL显著上调。用地诺单抗中和RANKL可显著消除BRCA1单倍体不足细胞在非贴壁/非分化条件下作为漂浮微肿瘤或“乳腺球”存活和增殖的能力，这是CSC相对比例和存活的公认替代指标。有趣的是，由上皮-间质转化或HER2过表达特征驱动的CSC样状态对地诺单抗有一定反应。我们提出，BRCA1在乳腺上皮中的特异性单等位基因失活可能足以自主产生对RANKL成瘾、对地诺单抗敏感的CSC样状态。来自基因不同的乳腺癌亚型的CSC样状态对过度活跃的RANKL / RANK轴的趋同成瘾可能开创一个基于地诺单抗作为CSC靶向药物的癌症预防和治疗新时代。
