雌激素受体α (ERα) 在乳腺癌的病因、进展和治疗中发挥着核心作用。 ESR1 配体结合域 (LBD) 中的组成性激活体细胞突变 Y537S 和 D538G 与内分泌治疗的获得性耐药相关。我们之前已经证明金属雌激素钙通过与受体的 LBD 相互作用来激活 ERα。这项研究表明，镉通过类似于钙的机制激活 ERα，并有助于并进一步增强 ERα 突变体 Y537S 和 D538G 的组成活性。突变分析确定 LBD 溶剂可及表面上的 C381、N532A、H516A/N519A/E523A 和 E542/D545A 可能是钙/金属相互作用位点。与雌二醇不增加Y537S和D538G突变体的活性相反，镉增加了组成型突变体的活性。 Y537S和D538G突变体中钙/金属相互作用位点的突变导致组成活性和镉诱导的活性显着降低。 wtERα 中钙/金属相互作用位点的突变减少了受体与雌激素响应基因增强子的结合以及核受体辅激活子 1 和 RNA 聚合酶 II 的结合。与wtERα相反，Y537S和D538G突变体中钙/金属相互作用位点的突变并没有减少与DNA的结合，但阻止了与共激活剂和聚合酶的稳定相互作用。生长测定进一步表明，钙通道阻滞剂和螯合剂显着降低了表达这些组成型活性突变体的 MCF7 细胞的生长。综上所述，结果表明，镉暴露在乳腺癌的病因、进展和治疗反应中发挥着重要作用，部分原因在于镉能够激活 ERα。版权所有 © 2024 Psaltis, Wang, Yan, Gahtani, Huang 、哈达德和马丁。

The estrogen receptor alpha (ERα) plays a central role in the etiology, progression, and treatment of breast cancers. Constitutively activating somatic mutations Y537S and D538G, in the ligand binding domain (LBD) of ESR1, are associated with acquired resistance to endocrine therapies. We have previously shown that the metalloestrogen calcium activates ERα through an interaction with the LBD of the receptor. This study shows that cadmium activates ERα through a mechanism similar to calcium and contributes to, and further increases, the constitutive activity of the ERα mutants Y537S and D538G. Mutational analysis identified C381, N532A, H516A/N519A/E523A, and E542/D545A on the solvent accessible surface of the LBD as possible calcium/metal interaction sites. In contrast to estradiol, which did not increase the activity of the Y537S and D538G mutants, cadmium increased the activity of the constitutive mutants. Mutation of the calcium/metal interaction sites in Y537S and D538G mutants resulted in a significant decrease in constitutive activity and cadmium induced activity. Mutation of calcium/metal interaction sites in wtERα diminished binding of the receptor to the enhancer of estrogen responsive genes and the binding of nuclear receptor coactivator 1 and RNA polymerase II. In contrast to wtERα, mutation of the calcium/metal interaction sites in the Y537S and D538G mutants did not diminish binding to DNA but prevented a stable interaction with the coactivator and polymerase. Growth assays further revealed that calcium channel blockers and chelators significantly decreased the growth of MCF7 cells expressing these constitutively active mutants. Taken together, the results suggest that exposure to cadmium plays a role in the etiology, progression, and response to treatment of breast cancer due, in part, to its ability to activate ERα.Copyright © 2024 Psaltis, Wang, Yan, Gahtani, Huang, Haddad and Martin.