Department of Circulation and Medical Imaging, NTNU, Trondheim, Norway.
Department of Tumor Biology, Institute for Cancer Research, Radiumhospital, Oslo University Hospital, Oslo, Norway.
Sci Rep. 2020 Oct 12;10(1):16992. doi: 10.1038/s41598-020-74083-z.
In this study, we probed the importance of O-GlcNAc transferase (OGT) activity for the survival of tamoxifen-sensitive (TamS) and tamoxifen-resistant (TamR) breast cancer cells. Tamoxifen is an antagonist of estrogen receptor (ERα), a transcription factor expressed in over 50% of breast cancers. ERα-positive breast cancers are successfully treated with tamoxifen; however, a significant number of patients develop tamoxifen-resistant disease. We show that in vitro development of tamoxifen-resistance is associated with increased sensitivity to the OGT small molecule inhibitor OSMI-1. Global transcriptome profiling revealed that TamS cells adapt to OSMI-1 treatment by increasing the expression of histone genes. This is known to mediate chromatin compaction. In contrast, TamR cells respond to OGT inhibition by activating the unfolded protein response and by significantly increasing ERRFI1 expression. ERRFI1 is an endogenous inhibitor of ERBB-signaling, which is a known driver of tamoxifen-resistance. We show that ERRFI1 is selectively downregulated in ERα-positive breast cancers and breast cancers driven by ERBB2. This likely occurs via promoter methylation. Finally, we show that increased ERRFI1 expression is associated with extended survival in patients with ERα-positive tumors (p = 9.2e-8). In summary, we show that tamoxifen-resistance is associated with sensitivity to OSMI-1, and propose that this is explained in part through an epigenetic activation of the tumor-suppressor ERRFI1 in response to OSMI-1 treatment.
在这项研究中，我们探讨了 O-连接的 N-乙酰氨基葡萄糖转移酶（OGT）活性对他莫昔芬敏感（TamS）和他莫昔芬耐药（TamR）乳腺癌细胞存活的重要性。他莫昔芬是雌激素受体（ERα）的拮抗剂，ERα 在超过 50%的乳腺癌中表达。ERα 阳性乳腺癌用他莫昔芬治疗效果显著；然而，相当数量的患者出现他莫昔芬耐药疾病。我们表明，体外他莫昔芬耐药的发展与对 OGT 小分子抑制剂 OSMI-1 的敏感性增加有关。全转录组谱分析显示，TamS 细胞通过增加组蛋白基因的表达来适应 OSMI-1 治疗。这被认为介导染色质紧缩。相比之下，TamR 细胞通过激活未折叠蛋白反应并显著增加 ERRFI1 的表达来响应 OGT 抑制。ERRFI1 是 ERBB 信号的内源性抑制剂，是他莫昔芬耐药的已知驱动因素。我们表明，ERRFI1 在 ERα 阳性乳腺癌和 ERBB2 驱动的乳腺癌中选择性地下调。这可能通过启动子甲基化发生。最后，我们表明，ERRFI1 表达增加与 ERα 阳性肿瘤患者的生存延长相关（p=9.2e-8）。总之，我们表明，他莫昔芬耐药与对 OSMI-1 的敏感性有关，并提出这部分是通过 OSMI-1 治疗对肿瘤抑制因子 ERRFI1 的表观遗传激活来解释的。
