Molecular Oncology, Spanish National Cancer Research Centre (CNIO), Madrid, Spain.
Oncobell, Bellvitge Biomedical Research Institute (IDIBELL), Barcelona, Spain.
EMBO Mol Med. 2023 Apr 11;15(4):e16715. doi: 10.15252/emmm.202216715. Epub 2023 Mar 7.
Despite strong preclinical data, the therapeutic benefit of the RANKL inhibitor, denosumab, in breast cancer patients, beyond the bone, is unclear. Aiming to select patients who may benefit from denosumab, we hereby analyzed RANK and RANKL protein expression in more than 2,000 breast tumors (777 estrogen receptor-negative, ER ) from four independent cohorts. RANK protein expression was more frequent in ER tumors, where it associated with poor outcome and poor response to chemotherapy. In ER breast cancer patient-derived orthoxenografts (PDXs), RANKL inhibition reduced tumor cell proliferation and stemness, regulated tumor immunity and metabolism, and improved response to chemotherapy. Intriguingly, tumor RANK protein expression associated with poor prognosis in postmenopausal breast cancer patients, activation of NFKB signaling, and modulation of immune and metabolic pathways, suggesting that RANK signaling increases after menopause. Our results demonstrate that RANK protein expression is an independent biomarker of poor prognosis in postmenopausal and ER breast cancer patients and support the therapeutic benefit of RANK pathway inhibitors, such as denosumab, in breast cancer patients with RANK ER tumors after menopause.
尽管有强有力的临床前数据，但 RANKL 抑制剂地舒单抗在乳腺癌患者中的治疗益处（超出骨骼方面）尚不清楚。为了选择可能受益于地舒单抗的患者，我们在此分析了来自四个独立队列的 2000 多个乳腺癌肿瘤（777 个雌激素受体阴性，ER）中的 RANK 和 RANKL 蛋白表达。RANK 蛋白表达在 ER 肿瘤中更为常见，与不良预后和对化疗反应不良相关。在 ER 乳腺癌患者来源的异种移植瘤（PDXs）中，RANKL 抑制减少了肿瘤细胞增殖和干性，调节了肿瘤免疫和代谢，并改善了对化疗的反应。有趣的是，肿瘤 RANK 蛋白表达与绝经后乳腺癌患者的不良预后、NFKB 信号通路的激活以及免疫和代谢途径的调节相关，表明绝经后 RANK 信号通路增加。我们的研究结果表明，RANK 蛋白表达是绝经后和 ER 乳腺癌患者不良预后的独立生物标志物，并支持 RANK 通路抑制剂（如地舒单抗）在绝经后具有 RANKER 肿瘤的乳腺癌患者中的治疗益处。
