UKM Medical Molecular Biology Institute (UMBI), University Kebangsaan Malaysia Medical Centre, Jalan Ya'acob Latiff, Bandar Tun Razak, Cheras, 56000, Kuala Lumpur, Malaysia.
Mol Biol Rep. 2019 Dec;46(6):6617-6624. doi: 10.1007/s11033-019-05079-w. Epub 2019 Sep 24.
FEC chemo-resistance in triple negative breast cancer (TNBC) remains a challenge. Therefore it is crucial to determine the right treatment regime by understanding molecular mechanisms of driver regulators involved in the progression of TNBCs. This study aims to understand SETD1A mechanisms in TNBC development in two TNBC cell lines. SETD1A was transiently transfected in MDA-MB-468 (FEC good prognosis) and Hs578T (FEC poor prognosis). Regulation of potential targets miR205, EMT marker ZEB1 and LRG1 and proliferative marker Ki-67 were tested by RqPCR to elucidate SETD1A interactions. This study displayed significant recovery of miR205 with SETD1A depletion and reduction of ZEB1 in MDA-MB-468. However, ZEB1 remained unchanged in Hs578T indicating ZEB1 regulation may be outcompeted by other mechanisms associated with aggressive cell line characteristics and the expression of endogenous ZEB1 was relatively high in Hs578T. Elevation of LRG1 and declined Ki-67 were observed by SETD1A knocked down. Enhanced expression was observed by LRG1 in Hs578T and not in MDA-MB-468 suggesting LRG1 contributed to distinct poor FEC outcome in TNBCs. The underlying mechanism of SETD1A in miR205/ZEB1/Ki-67/LRG1 axis needs further evaluation. Whether abrogation of the pathway is indeed associated with transcriptional or post-transcriptional activation in TNBC cell lines models, clearly validation in clinical samples is warranted to achieve its prognostic and therapeutic values in TNBCs.
三阴性乳腺癌（TNBC）的 FEC 耐药仍然是一个挑战。因此，通过了解参与 TNBC 进展的驱动调节因子的分子机制，确定正确的治疗方案至关重要。本研究旨在了解 SETD1A 在两种 TNBC 细胞系中的 TNBC 发展中的作用机制。在 MDA-MB-468（FEC 预后良好）和 Hs578T（FEC 预后不良）中转染 SETD1A 瞬时表达。通过 RqPCR 测试潜在靶标 miR205、EMT 标志物 ZEB1 和 LRG1 以及增殖标志物 Ki-67 的表达，以阐明 SETD1A 的相互作用。本研究显示，在 MDA-MB-468 中，SETD1A 耗竭后 miR205 显著恢复，ZEB1 减少。然而，在 Hs578T 中 ZEB1 不变，表明 ZEB1 的调节可能被与侵袭性细胞系特征相关的其他机制所竞争，并且 Hs578T 中内源性 ZEB1 的表达相对较高。SETD1A 敲低后观察到 LRG1 升高和 Ki-67 下降。在 Hs578T 中观察到 LRG1 的增强表达，而在 MDA-MB-468 中则没有，表明 LRG1 导致 TNBC 中 FEC 不良结局的不同。SETD1A 在 miR205/ZEB1/Ki-67/LRG1 轴中的潜在机制需要进一步评估。该途径的阻断是否确实与 TNBC 细胞系模型中的转录或转录后激活有关，显然需要在临床样本中进行验证，以实现其在 TNBC 中的预后和治疗价值。
