Laboratory of Molecular Medicine, Division of Cancer Research, Regional Cancer Centre (Research Centre, University of Kerala), Thiruvananthapuram, 695011, Kerala, India.
Division of Cancer Biology, Rajiv Gandhi Centre for Biotechnology, Poojappura, Thiruvananthapuram, 695014, India.
Med Oncol. 2023 Apr 4;40(5):137. doi: 10.1007/s12032-023-02007-8.
Aside from the high prevalence of incidents of breast cancer, the high grade of heterogeneity and the dearth of standard treatment guidelines make triple-negative breast cancer (TNBC) the most refractory subtype. Though still in its infancy, the Hippo pathway has been known to play a critical role in tumorigenesis. However, the molecular mechanics through which the pathway exploits the breast cancer (BC) cell vulnerability are largely unexplored. In this study, we observed a relatively higher expression of the Hippo effector, yes-associated protein (YAP), in TNBC patients compared to non-TNBC patients. Thus, we sought to investigate the contribution of Hippo signaling in TNBC by focusing particularly on transducers of the pathway. Impeding YAP transactivation by means of RNA interference or pharmacological inhibition was carried out, followed by evaluation of the subsequent biological changes at the molecular level. We successfully translated the observed data into a TNBC patient-derived xenograft cell line (PDXC). We discovered that nuclear translocation of YAP was associated with TNBC aggressive characteristics and activated the EGFR-AKT axis. Here, we explored the putative role of the Hippo transducer in enhancing cancer hostility and observed that YAP transduction drives proliferation, migration, and survival of TNBC by preventing cellular apoptosis through mediating EGFR activation. These observations suggest that YAP represents a major vulnerability in TNBC cells that may be exploited therapeutically.
除了乳腺癌发病率高外，高度异质性和缺乏标准治疗指南使得三阴性乳腺癌（TNBC）成为最难治疗的亚型。尽管 Hippo 通路仍处于起步阶段，但已知其在肿瘤发生中起着关键作用。然而，该通路利用乳腺癌（BC）细胞脆弱性的分子机制在很大程度上仍未被探索。在这项研究中，我们观察到 TNBC 患者中 Hippo 效应物 yes 相关蛋白（YAP）的表达相对较高，而非 TNBC 患者。因此，我们试图通过特别关注该通路的转导器来研究 Hippo 信号在 TNBC 中的作用。通过 RNA 干扰或药理学抑制来阻碍 YAP 的转录激活，然后在分子水平上评估随后的生物学变化。我们成功地将观察到的数据转化为 TNBC 患者来源的异种移植细胞系（PDXC）。我们发现 YAP 的核易位与 TNBC 的侵袭性特征有关，并激活了 EGFR-AKT 轴。在这里，我们探讨了 Hippo 转导器在增强癌症侵袭性中的潜在作用，并观察到 YAP 转导通过介导 EGFR 激活来阻止细胞凋亡，从而促进 TNBC 的增殖、迁移和存活。这些观察结果表明，YAP 代表了 TNBC 细胞中的一个主要弱点，可能在治疗上被利用。
