尽管已成功将治疗方法组合应用于改善雌激素受体 α（ER+）乳腺癌患者的转移性疾病的生存率，但获得性内分泌耐药的机制尚未完全阐明。核糖核酸结合蛋白 HNRNPA2B1（A2B1）是转录RNA中 N(6)-甲基腺苷（m6A）的识别蛋白，在内分泌耐药的ER+ LCC9和LY2细胞中表达上调，与母细胞MCF-7内分泌敏感型乳腺癌细胞相比，该细胞为光泽A乳腺癌细胞。我们分析了过表达A2B1的MCF-7细胞的miRNA-seq转录组，鉴定了丝氨酸代谢途径。丝氨酸合成途径（SSP）中两个关键酶，磷酸丝氨酸氨基转移酶 1（PSAT1）和磷酸甘油醛酸脱氢酶（PHGDH）在接受替莫西芬（TAM）治疗的ER+乳腺癌患者中与不良预后相关。我们报告了LCC9和LY2细胞中PSAT1和PHGDH的表达水平高于MCF-7细胞，并且它们的敲除增强了这些耐药细胞对TAM的敏感性。本研究展示了在MCF-7细胞中稳定、适度过表达A2B1会增加PSAT1和PHGDH的表达，从而导致内分泌耐药。我们在MCF-7-A2B1细胞中鉴定了4个miRNA，它们通过双荧光素酶检测实验证实直接靶向PSAT1的3'UTR(miR-145-5p和miR-424-5p)，以及PHGDH的3'UTR(miR-34b-5p和miR-876-5p)。LCC9和ZR-75-1-4-OHT细胞中miR-145-5p和miR-424-5p的表达下调与PSAT1的上调相关，而LCC9和ZR-75-1-4-OHT细胞中miR-34b-5p和miR-876-5p的表达下调与PHGDH的上调相关。转染这些miRNA可恢复LCC9和ZR-75-1-4-OHT细胞对内分泌治疗的敏感性。总的来说，我们的数据表明A2B1调控的miRNA的下调在内分泌耐药中起作用，并且SSP的上调促进了ER+乳腺癌的肿瘤进展。

Despite the successful combination of therapies improving survival of estrogen receptor α (ER+) breast cancer patients with metastatic disease, mechanisms for acquired endocrine resistance remain to be fully elucidated. The RNA binding protein HNRNPA2B1 (A2B1), a reader of N(6)-methyladenosine (m6A) in transcribed RNA, is upregulated in endocrine-resistant, ER+ LCC9 and LY2 cells compared to parental MCF-7 endocrine-sensitive luminal A breast cancer cells. The miRNA-seq transcriptome of MCF-7 cells overexpressing A2B1 identified the serine metabolic processes pathway. Increased expression of two key enzymes in the serine synthesis pathway (SSP), phosphoserine aminotransferase 1 (PSAT1) and phosphoglycerate dehydrogenase (PHGDH), correlate with poor outcomes in ER+ breast patients who received tamoxifen (TAM). We reported that PSAT1 and PHGDH were higher in LCC9 and LY2 cells compared to MCF-7 cells and their knockdown enhanced TAM-sensitivity in these-resistant cells. Here we demonstrate that stable, modest overexpression of A2B1 in MCF-7 cells increased PSAT1 and PHGDH and endocrine-resistance. We identified four miRNAs downregulated in MCF-7-A2B1 cells that directly target the PSAT1 3'UTR (miR-145-5p and miR-424-5p), and the PHGDH 3'UTR (miR-34b-5p and miR-876-5p) in dual luciferase assays. Lower expression of miR-145-5p and miR-424-5p in LCC9 and ZR-75-1-4-OHT cells correlated with increased PSAT1 and lower expression of miR-34b-5p and miR-876-5p in LCC9 and ZR-75-1-4-OHT cells correlated with increased PHGDH. Transient transfection of these miRNAs restored endocrine-therapy sensitivity in LCC9 and ZR-75-1-4-OHT cells. Overall, our data suggest a role for decreased A2B1-regulated miRNAs in endocrine-resistance and upregulation of the SSP to promote tumor progression in ER+ breast cancer.