IRCCS - Regina Elena National Cancer Institute, Translational Oncology Research Unit, Via Elio Chianesi 53, 00144, Rome, Italy.
IRCCS - Regina Elena National Cancer Institute, Clinical Trial Center, Biostatistics and Bioinformatics Unit, Via Elio Chianesi 53, 00144, Rome, Italy.
J Exp Clin Cancer Res. 2024 Mar 9;43(1):75. doi: 10.1186/s13046-024-02998-w.
Breast Cancer (BC) can be classified, due to its heterogeneity, into multiple subtypes that differ for prognosis and clinical management. Notably, triple negative breast cancer (TNBC) - the most aggressive BC form - is refractory to endocrine and most of the target therapies. In this view, taxane-based therapy still represents the elective strategy for the treatment of this tumor. However, due variability in patients' response, management of TNBC still represents an unmet medical need. Telomeric Binding Factor 2 (TRF2), a key regulator of telomere integrity that is over-expressed in several tumors, including TNBC, has been recently found to plays a role in regulating autophagy, a degradative process that is involved in drug detoxification. Based on these considerations, we pointed, here, at investigating if TRF2, regulating autophagy, can affect tumor sensitivity to therapy.
Human TNBC cell lines, over-expressing or not TRF2, were subjected to treatment with different taxanes and drug efficacy was tested in terms of autophagic response and cell proliferation. Autophagy was evaluated first biochemically, by measuring the levels of LC3, and then by immunofluorescence analysis of LC3-puncta positive cells. Concerning the proliferation, cells were subjected to colony formation assays associated with western blot and FACS analyses. The obtained results were then confirmed also in mouse models. Finally, the clinical relevance of our findings was established by retrospective analysis on a cohort of TNBC patients subjected to taxane-based neoadjuvant chemotherapy.
This study demonstrated that TRF2, inhibiting autophagy, is able to increase the sensitivity of TNBC cells to taxanes. The data, first obtained in in vitro models, were then recapitulated in preclinical mouse models and in a cohort of TNBC patients, definitively demonstrating that TRF2 over-expression enhances the efficacy of taxane-based neoadjuvant therapy in reducing tumor growth and its recurrence upon surgical intervention.
Based on our finding it is possible to conclude that TRF2, already known for its role in promoting tumor formation and progression, might represents an Achilles' heel for cancer. In this view, TRF2 might be exploited as a putative biomarker to predict the response of TNBC patients to taxane-based neoadjuvant chemotherapy.
乳腺癌（BC）因其异质性可分为多种亚型，这些亚型在预后和临床管理方面存在差异。值得注意的是，三阴性乳腺癌（TNBC）是最具侵袭性的 BC 形式，对内分泌和大多数靶向治疗均具有抗性。在这种情况下，基于紫杉烷的治疗仍然是治疗这种肿瘤的首选策略。然而，由于患者反应的可变性，TNBC 的管理仍然是未满足的医疗需求。端粒结合因子 2（TRF2）是端粒完整性的关键调节剂，在包括 TNBC 在内的几种肿瘤中过度表达，最近发现它在调节自噬中发挥作用，自噬是一种参与药物解毒的降解过程。基于这些考虑，我们在这里指出，TRF2 是否通过调节自噬来影响肿瘤对治疗的敏感性。
过表达或不表达 TRF2 的人 TNBC 细胞系接受不同紫杉烷的治疗，并根据自噬反应和细胞增殖来测试药物疗效。自噬首先通过测量 LC3 的水平进行生化评估，然后通过 LC3 阳性细胞的免疫荧光分析进行评估。关于增殖，细胞进行集落形成测定，并结合 western blot 和 FACS 分析。然后在小鼠模型中证实了获得的结果。最后，通过对接受紫杉烷类新辅助化疗的 TNBC 患者队列进行回顾性分析，确定了我们研究结果的临床相关性。
这项研究表明，TRF2 通过抑制自噬，能够增加 TNBC 细胞对紫杉烷的敏感性。首先在体外模型中获得的数据随后在临床前小鼠模型和 TNBC 患者队列中得到了重现，最终证明 TRF2 过表达增强了基于紫杉烷的新辅助治疗在减少肿瘤生长及其在手术干预后复发方面的疗效。
基于我们的发现，可以得出结论，TRF2 已知其在促进肿瘤形成和进展中的作用，可能是癌症的致命弱点。在这种情况下，TRF2 可能被用作预测 TNBC 患者对基于紫杉烷的新辅助化疗反应的潜在生物标志物。
