ISPB, Faculté de Pharmacie, Lyon, France; Université Lyon 1, Lyon, France; INSERM U1052, CNRS UMR5286, Centre de Recherche en Cancérologie de Lyon, Lyon, France.
Université Lyon 1, Lyon, France; INSERM U1052, CNRS UMR5286, Centre de Recherche en Cancérologie de Lyon, Lyon, France.
Mol Oncol. 2014 Dec;8(8):1441-57. doi: 10.1016/j.molonc.2014.05.013. Epub 2014 Jun 10.
We aimed at highlighting the role of ZNF217, a Krüppel-like finger protein, in Estrogen Receptor-α (ERα)-positive (ER+) and luminal breast cancers. Here we report for the first time that ZNF217 and ERα proteins bind to each other in both breast cancer cells and breast tumour samples, via the ERα hinge domain and the ZNF217 C-terminal domain. ZNF217 enhances the recruitment of ERα to its estrogen response elements (ERE) and the ERα-dependent transcription of the GREB1 estrogen-regulated gene. The prognostic power of ZNF217 mRNA expression levels is most discriminatory in breast cancers classified with a "good prognosis", particularly the Luminal-A subclass. A new immunohistochemistry ZNF217 index, based on nuclear and cytoplasmic ZNF217 staining, also allowed the identification of intermediate/poor relapse-free survivors in the Luminal-A subgroup. ZNF217 confers tamoxifen resistance in ER+ breast cancer cells and is a predictor of relapse under endocrine therapy in patients with ER+ breast cancer. ZNF217 thus allows the re-stratification of patients with ER+ breast cancers considered as cancers with good prognosis where no other biomarkers are currently available and widely used. Here we propose a model in ER+ breast cancer where ZNF217-driven aggressiveness incorporates ZNF217 as a positive enhancer of ERα direct genomic activity and where ZNF217 possesses its highest discriminatory prognostic value.
我们旨在强调锌指蛋白 217（ZNF217）在雌激素受体-α（ERα）阳性（ER+）和腔面乳腺癌中的作用。在这里，我们首次报道 ZNF217 和 ERα 蛋白通过 ERα 铰链结构域和 ZNF217 C 端结构域相互结合，存在于乳腺癌细胞和乳腺肿瘤样本中。ZNF217 增强了 ERα 向其雌激素反应元件（ERE）的募集和 ERα 依赖性 GREB1 雌激素调节基因的转录。ZNF217 mRNA 表达水平的预后能力在具有“良好预后”的乳腺癌中最具区分性，尤其是 Luminal-A 亚类。一种新的基于核和细胞质 ZNF217 染色的免疫组织化学 ZNF217 指数，也能够在 Luminal-A 亚组中识别出中等/不良无复发生存者。ZNF217 在 ER+乳腺癌细胞中赋予他莫昔芬耐药性，并且是 ER+乳腺癌患者内分泌治疗后复发的预测因子。因此，ZNF217 允许对被认为具有良好预后的 ER+乳腺癌患者进行重新分层，而目前尚无其他生物标志物可供广泛使用。在这里，我们提出了一个 ER+乳腺癌模型，其中 ZNF217 驱动的侵袭性将 ZNF217 作为 ERα 直接基因组活性的正增强子，并且 ZNF217 具有最高的预后区分价值。
