Abstract:
Oestrogen receptor alpha (ER; gene symbol ESR1) is the most important prognostic and treatment-predictive biomarker in breast cancer. Drugs targeting oestrogen and ER for endocrine therapy of breast cancer include aromatase inhibitors, the selective ER modulator tamoxifen and the selective ER degrader fulvestrant. Tumours can develop resistance to endocrine therapy through several mechanisms, which is often linked to altered expression of ER. To investigate the role of promoter methylation in the regulation of ESR1 expression, we used bisulfite sequencing to measure methylation at CpG sites in alternative ER promoter regions for six cell line models of fulvestrant resistance. Both CpG methylation and expression of alternative first exons changed dynamically, with striking differences between cell lines that had stable or unstable resistance upon fulvestrant withdrawal. Methylation at some CpG sites was strongly negatively correlated with expression of specific first exons. In a breast tumour cohort, higher relative expression of upstream alternative first exons was associated with worse prognosis in post-menopausal women with ER-positive tumours who received endocrine therapy.
摘要:
雌激素受体α(ER;基因符号ESR1)是乳腺癌中最重要的预后和治疗预测生物标志物。乳腺癌内分泌治疗的靶向雌激素和ER的药物包括芳香化酶抑制剂,选择性ER调节剂他莫昔芬和选择性ER降解剂氟维司群。肿瘤可以通过几种机制对内分泌治疗产生抗药性,这通常与ER的表达改变有关。探讨启动子甲基化在ESR1表达调控中的作用,我们使用亚硫酸氢盐测序来测量氟维司群耐药的6个细胞系模型的替代ER启动子区域CpG位点的甲基化.CpG甲基化和替代第一外显子的表达均动态变化,氟维司群停药后具有稳定或不稳定抗性的细胞系之间存在显着差异。某些CpG位点的甲基化与特定第一外显子的表达呈强烈负相关。在一个乳腺肿瘤队列中,在接受内分泌治疗的绝经后ER阳性肿瘤女性中,上游替代第一外显子的相对高表达与预后较差相关.