雌激素受体α（ER；基因符号ESR1）是乳腺癌最重要的预后和治疗预测生物标志物。用于乳腺癌内分泌治疗的针对雌激素和 ER 的药物包括芳香酶抑制剂、选择性 ER 调节剂他莫昔芬和选择性 ER 降解剂氟维司群。肿瘤可以通过多种机制对内分泌治疗产生耐药性，这通常与 ER 表达的改变有关。为了研究启动子甲基化在 ESR1 表达调节中的作用，我们使用亚硫酸氢盐测序来测量氟维司群耐药细胞系模型的替代 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都动态变化，在氟维司群停药后具有稳定或不稳定耐药性的细胞系之间存在显着差异。一些 CpG 位点的甲基化与特定第一外显子的表达呈强烈负相关。在乳腺肿瘤队列中，上游替代第一外显子的较高相对表达与接受内分泌治疗的 ER 阳性肿瘤绝经后女性的较差预后相关。© 2024 作者。约翰·威利出版的《分子肿瘤学》

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.© 2024 The Author(s). Molecular Oncology published by John Wiley & Sons Ltd on behalf of Federation of European Biochemical Societies.