Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, Taipei, Taiwan; Department of Biochemistry and Molecular Cell Biology, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan.
Department of Biochemistry and Molecular Cell Biology, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan.
Pharmacol Res. 2024 Nov;209:107429. doi: 10.1016/j.phrs.2024.107429. Epub 2024 Sep 19.
Triple-negative breast cancer (TNBC) is the most malignant breast cancer subtype, characterized with high aggressiveness and a high recurrence rate. Olaparib is the first US Food and Drug Administration-approved poly(ADP ribose) polymerase (PARP) inhibitor (PARPi) to treat breast cancer patients with a germline BRCA1 or BRCA2 mutation. However, resistance to Olaparib treatment restricts the therapeutic effects, and thus novel therapeutics are urgently required. In the present study, we identified that the combination of melatonin and Olaparib synergistically enhanced the sensitivity of TNBC cells. Moreover, melatonin exerted promising antitumor activities in Olaparib-resistant cells, implying the potential for its clinical application. An RNA-sequencing analysis revealed that melatonin treatment downregulated laminin subunit beta 3 (LAMB3) expression. Genetic ablation of LAMB3 significantly increased Olaparib sensitivity, and subsequently suppressed proliferation, epithelial-to-mesenchymal transition (EMT)-related gene expressions, and aggressiveness of breast cancer cells. Accordingly, LAMB3 expression was positively correlated with C-X-C motif chemokine ligand 2 (CXCL2), and they collaboratively promoted cancer-associated fibroblast (CAF) infiltration. An in vivo study demonstrated that combined treatment with melatonin and Olaparib showed enhanced inhibitory efficacy against tumor growth, LAMB3 expression, CXCL2 levels, and CAF infiltration compared to single treatment groups, and combined treatment with melatonin and Olaparib significantly ameliorated the immunosuppressive tumor microenvironment. These findings illustrate a promising therapeutic strategy using melatonin to overcome Olaparib resistance and activate antitumor immunity via attenuating the LAMB3-CXCL2 axis in breast cancer patients.
三阴性乳腺癌（TNBC）是最恶性的乳腺癌亚型，具有高度侵袭性和高复发率的特点。奥拉帕利是美国食品和药物管理局（FDA）批准的首个用于治疗携带种系 BRCA1 或 BRCA2 突变的乳腺癌患者的聚（ADP 核糖）聚合酶（PARP）抑制剂（PARPi）。然而，奥拉帕利治疗的耐药性限制了其治疗效果，因此急需新的治疗方法。本研究发现，褪黑素与奥拉帕利联合使用可协同增强 TNBC 细胞的敏感性。此外，褪黑素在奥拉帕利耐药细胞中表现出有希望的抗肿瘤活性，暗示其具有临床应用的潜力。RNA 测序分析显示，褪黑素处理可下调层粘连蛋白亚基β3（LAMB3）的表达。LAMB3 的基因敲除显著增加了奥拉帕利的敏感性，并随后抑制了乳腺癌细胞的增殖、上皮间质转化（EMT）相关基因表达和侵袭性。因此，LAMB3 的表达与 C-X-C 基序趋化因子配体 2（CXCL2）呈正相关，它们协同促进癌症相关成纤维细胞（CAF）浸润。体内研究表明，与单独治疗组相比，褪黑素和奥拉帕利联合治疗可增强对肿瘤生长、LAMB3 表达、CXCL2 水平和 CAF 浸润的抑制作用，联合治疗可显著改善免疫抑制性肿瘤微环境。这些发现表明，褪黑素联合治疗是一种很有前途的治疗策略，可通过抑制乳腺癌患者的 LAMB3-CXCL2 轴来克服奥拉帕利耐药性并激活抗肿瘤免疫。
