Department of Gynecology and Obstetrics, University Medical Center Regensburg, Regensburg, Germany.
Second Department of Gynecology, Medical University of Lublin, Lublin, Poland.
Arch Gynecol Obstet. 2021 Jul;304(1):203-213. doi: 10.1007/s00404-020-05902-x. Epub 2021 Jan 3.
Human gene icb-1 recently has been reported to be part of a gene expression score predicting response to antiestrogen fulvestrant in breast cancer patients. In the present study, we examined to what extent icb-1 expression would affect the response of breast cancer cells to this antiestrogen in vitro and investigated underlying molecular mechanisms. Using open access mRNA data, we elucidated the significance of icb-1 expression for survival of breast cancer patients.
Icb-1 gene expression was knocked down by RNAi. Breast cancer cell growth after treatment with fulvestrant was assessed using the Cell Titer Blue assay. Gene expression was analyzed by Western blot analysis or RT-qPCR. Survival analyses were performed using bioinformatical online tools and data.
Knockdown of icb-1 in T-47D breast cancer cells significantly increased growth of this cell line and also elevated the growth-stimulatory effect of E2 (p < 0.001). After treatment with different concentrations of fulvestrant, icb-1 knockdown cells exhibited a significantly enhanced response to this drug (p < 0.01). On the molecular level, icb-1 knockdown led to elevated expression of ESR1 and its target gene TFF1 (pS2) and enhanced E2-triggered up-regulation of proliferation genes. Finally, bioinformatical meta-analysis of gene expression data of 3951 breast cancer patients revealed that high icb-1 expression increases their relapse-free survival (HR = 0.87, p < 0.05).
The presented data further support a tumor-suppressive role of icb-1 in breast cancer and suggest an inhibitory effect of this gene on fulvestrant action, which both are suggested to be mediated by suppression of cellular E2 response.
人类基因 icb-1 最近被报道是预测乳腺癌患者对抗雌激素氟维司群反应的基因表达评分的一部分。在本研究中，我们研究了 icb-1 表达在多大程度上会影响乳腺癌细胞对这种抗雌激素的体外反应，并探讨了潜在的分子机制。利用公开获取的 mRNA 数据，我们阐明了 icb-1 表达对乳腺癌患者生存的意义。
通过 RNAi 敲低 icb-1 基因表达。使用 Cell Titer Blue 测定法评估氟维司群处理后乳腺癌细胞的生长情况。通过 Western blot 分析或 RT-qPCR 分析基因表达。使用生物信息学在线工具和数据进行生存分析。
在 T-47D 乳腺癌细胞中敲低 icb-1 显著增加了该细胞系的生长，并增强了 E2 的生长刺激作用（p<0.001）。用不同浓度的氟维司群处理后，icb-1 敲低细胞对该药物的反应明显增强（p<0.01）。在分子水平上，icb-1 敲低导致 ESR1 及其靶基因 TFF1（pS2）的表达升高，并增强了 E2 触发的增殖基因的上调。最后，对 3951 例乳腺癌患者的基因表达数据进行生物信息学荟萃分析显示，高 icb-1 表达增加了无复发生存率（HR=0.87，p<0.05）。
本研究进一步支持 icb-1 在乳腺癌中的肿瘤抑制作用，并提示该基因对氟维司群作用的抑制作用，这两种作用都被认为是通过抑制细胞 E2 反应介导的。
