背景:乳腺癌(BC)可以分类,由于其异质性,分为预后和临床管理不同的多种亚型。值得注意的是,三阴性乳腺癌(TNBC)-最具侵袭性的BC形式-对内分泌和大多数目标疗法都难以治疗。在这个观点中,基于紫杉烷的治疗仍然是治疗该肿瘤的选择性策略.然而,由于患者反应的变异性,TNBC的管理仍然代表着未满足的医疗需求。端粒结合因子2(TRF2),端粒完整性的关键调节因子在几种肿瘤中过度表达,包括TNBC,最近发现在调节自噬中起作用,涉及药物排毒的降解过程。基于这些考虑,我们指出,在这里,在调查TRF2是否调节自噬,会影响肿瘤对治疗的敏感性。
方法:人TNBC细胞系,过表达或不表达TRF2,接受不同紫杉烷类治疗,并根据自噬反应和细胞增殖测试药物功效。首先用生物化学方法评估自噬,通过测量LC3的水平,然后通过免疫荧光分析LC3-puncta阳性细胞。关于扩散,对细胞进行与蛋白质印迹和FACS分析相关的集落形成测定。然后在小鼠模型中也证实获得的结果。最后,我们的研究结果的临床相关性是通过对接受紫杉烷新辅助化疗的TNBC患者队列的回顾性分析确定的.
结果:本研究表明TRF2抑制自噬,能够增加TNBC细胞对紫杉烷的敏感性。数据,首次在体外模型中获得,然后在临床前小鼠模型和TNBC患者队列中进行概述,明确证明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和手术干预后复发方面的功效.
结论:根据我们的发现,可以得出结论,已知TRF2在促进肿瘤形成和进展中的作用,可能代表了癌症的致命弱点。在这个观点中,TRF2可能被用作推定的生物标志物来预测TNBC患者对基于紫杉烷的新辅助化疗的反应。
BACKGROUND: 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.
METHODS: 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.
RESULTS: 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.
CONCLUSIONS: 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.