雌激素受体α（ERα）阳性与激素依赖性乳腺癌的发展有密切关联。治疗这些癌症的主要挑战在于了解和克服内分泌耐药机制。最近发现，在细胞增殖和分化过程中存在两种不同的翻译程序，这些程序使用特定的转移核糖核酸（tRNA）库和密码子使用频率。考虑到癌细胞表型转换为更具增殖性和较少分化状态，我们可以推测tRNA库和密码子使用的改变可能使ERα编码序列不再适应，影响翻译速率、共翻译折叠和蛋白质的功能特性。为验证这一假设，我们生成了一个ERα同义编码序列，其密码子使用频率优化为在增殖细胞中特异表达的基因中观察到的频率，并调查编码的受体的功能性质。我们证明这样的密码子适应可以将ERα活性恢复到分化细胞中观察到的水平，包括：（a）增强转录激活功能1（AF1）在ERα转录活性中发挥的贡献；（b）增强与核受体共抑制因子1和2 [NCoR1和NCoR2（又名SMRT）]的相互作用，促进荧光素还原酶的能力；以及（c）降低与SRC原癌基因、非受体酪氨酸激酶（Src）和磷脂肌醇3-激酶（PI3K）p85激酶的相互作用，抑制MAPK和AKT信号通路。 ©2023 The Authors. Molecular Oncology 由John Wiley＆Sons Ltd代表欧洲生化联合会出版。

Oestrogen receptor-alpha (ERα) positivity is intimately associated with the development of hormone-dependent breast cancers. A major challenge in the treatment of these cancers is to understand and overcome the mechanisms of endocrine resistance. Recently, two distinct translation programmes using specific transfer RNA (tRNA) repertoires and codon usage frequencies were evidenced during cell proliferation and differentiation. Considering the phenotype switch of cancer cells to more proliferating and less-differentiated states, we can speculate that the changes in the tRNA pool and codon usage that likely occur make the ERα coding sequence no longer adapted, impacting translational rate, co-translational folding and the resulting functional properties of the protein. To verify this hypothesis, we generated an ERα synonymous coding sequence whose codon usage was optimized to the frequencies observed in genes expressed specifically in proliferating cells and then investigated the functional properties of the encoded receptor. We demonstrate that such a codon adaptation restores ERα activities to levels observed in differentiated cells, including: (a) an enhanced contribution exerted by transactivation function 1 (AF1) in ERα transcriptional activity; (b) enhanced interactions with nuclear receptor corepressor 1 and 2 [NCoR1 and NCoR2 (also known as SMRT) respectively], promoting repressive capability; and (c) reduced interactions with SRC proto-oncogene, non-receptor tyrosine kinase (Src) and phosphoinositide 3-kinase (PI3K) p85 kinases, inhibiting MAPK and AKT signalling pathway.© 2023 The Authors. Molecular Oncology published by John Wiley & Sons Ltd on behalf of Federation of European Biochemical Societies.