Kim Ji Yea, Park Chan Sub, Jang Se-Kyeong, Seol Hyesil, Seong Min-Ki, Noh Woo Chul, Park In-Chul, Kim Hyun-Ah
Division of Fusion Radiology Research, Korea Institute of Radiological and Medical Sciences, Seoul, Korea.
Department of Surgery, Korea Cancer Center Hospital, Korea Institute of Radiological and Medical Sciences, Seoul, Korea.
J Breast Cancer. 2022 Oct;25(5):387-403. doi: 10.4048/jbc.2022.25.e43.
Phosphorylated AKT1 (p-AKT1) at Ser473 is a functional isoform of AKT and a key component of the PI3K/mTOR/AKT pathway. This study aimed to evaluate the prognostic significance of p-AKT1 (Ser473) based on the molecular subtypes of breast cancer.
To investigate the prognostic value of p-AKT1 (Ser473), we performed a retrospective chart review of patients with breast cancer. Data on p-AKT1 (Ser473) positivity, hormone receptor (HR) status, human epidermal growth factor receptor 2 (HER2) expression status, and other clinicopathological factors were obtained. Furthermore, the therapeutic effect of blocking p-AKT1 (Ser473) in breast cancer cells was evaluated using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, cell apoptosis assay, apoptosis protein array, and western blot analysis.
A total of 3,044 patients were evaluated, and the median follow-up time was 43 (range: 0-125) months. In patients with HR-positive and HER2-positive disease, the p-AKT1 (Ser473)-positive group had worse disease-free survival (DFS) than the p-AKT1 (Ser473)-negative group (hazard ratio, 1.9; 95% confidence interval, 1.1-3.5; = 0.024). In the multivariate analysis, p-AKT1 (Ser473) remained a significantly worse prognostic factor in patients with HR-positive/HER2-positive breast cancer ( = 0.03). There was no difference in DFS according to p-AKT1 (Ser473) status among patients with other breast cancer subgroups. In vitro analysis showed that blocking p-AKT1 (Ser473) levels enhanced trastuzumab-induced cell death in HR-positive/HER2-positive and p-AKT1 (Ser473)-positive breast cancer cells.
p-AKT1 (Ser473) is a prognostic marker for poor outcomes in patients with HR-positive/HER2-positive breast cancer and may have a potential value as a therapeutic target.
丝氨酸473位点磷酸化的AKT1（p-AKT1）是AKT的一种功能性异构体，也是PI3K/mTOR/AKT信号通路的关键组成部分。本研究旨在基于乳腺癌的分子亚型评估p-AKT1（Ser473）的预后意义。
为研究p-AKT1（Ser473）的预后价值，我们对乳腺癌患者进行了回顾性病历审查。获取了关于p-AKT1（Ser473）阳性、激素受体（HR）状态、人表皮生长因子受体2（HER2）表达状态及其他临床病理因素的数据。此外，使用3-(4,5-二甲基噻唑-2-基)-2,5-二苯基四氮唑溴盐（MTT）法、细胞凋亡检测、凋亡蛋白芯片及蛋白质免疫印迹分析评估了阻断乳腺癌细胞中p-AKT1（Ser473）的治疗效果。
共评估了3044例患者，中位随访时间为43（范围：0 - 125）个月。在HR阳性且HER2阳性的疾病患者中，p-AKT1（Ser473）阳性组的无病生存期（DFS）比p-AKT1（Ser473）阴性组更差（风险比，1.9；95%置信区间，1.1 - 3.5；P = 0.024）。在多因素分析中，p-AKT1（Ser473）在HR阳性/HER2阳性乳腺癌患者中仍然是一个显著更差的预后因素（P = 0.03）。在其他乳腺癌亚组患者中，根据p-AKT1（Ser473）状态，DFS没有差异。体外分析表明，阻断p-AKT1（Ser473）水平可增强曲妥珠单抗诱导的HR阳性/HER2阳性且p-AKT1（Ser473）阳性乳腺癌细胞的死亡。
p-AKT1（Ser473）是HR阳性/HER2阳性乳腺癌患者预后不良的一个预后标志物，并且可能具有作为治疗靶点的潜在价值。
