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准独特的配体结合域结构特征降低DKK1在Y537SESR1突变乳腺癌细胞中的降低调节

K S Young¹, G R Hancock¹, E Fink¹

¹Department of Cancer Biology, Loyola University Chicago Stritch School of Medicine, Maywood, IL 50153.

bioRxiv : the preprint server for biology

|June 10, 2024

概括

像T6I-29这样的新选择性雌激素受体调节剂 (SERMs) 对抗内分泌抵抗性乳腺癌具有前景. 这项研究揭示了T6I-29降低了DKK1,这是雌激素受体阳性 (ER+) 乳腺癌中潜在的治疗点.

科学领域:

内分泌学在内分泌学.
在瘤学瘤学.
分子生物学分子生物学

背景情况:

内分泌治疗耐药性是雌激素受体阳性 (ER +) 乳腺癌治疗中的一个主要挑战.
雌激素受体α (ERα) 的突变,如Y537S,对标准疗法产生抗性,并促进转移.
下一代选择性雌激素受体调节剂 (SERMs) 和降解剂 (SERDs) 显示有效性,但往往没有持久的反应.

研究的目的:

综合评估新型SERM,T6I-29对携带Y537S ERα突变的乳腺癌细胞的活性.
调查T6I-29抗增殖效应背后的分子机制.
确定内分泌抵抗性ER+乳腺癌中的潜在新疗法标.

主要方法:

使用结构生物化学分析,体外实验和体外模型.
进行RNA测序以分析对T6I-29治疗反应的基因表达变化.
从乳腺癌患者和健康对照的血中测量DKK1水平.

主要成果:

T6I-29在Y537S ERα乳腺癌细胞中表现出显著的抗增殖活性.
T6I-29治疗导致DKK1的新型下调,DKK1是一种具有已知的致癌作用的糖蛋白.
与健康个体相比,DKK1在ER+乳腺癌患者的血中被发现是显著丰富的.

结论:

新型SERM T6I-29对Y537S ERα突变乳腺癌有效.
DKK1代表了内分泌抵抗性ER+乳腺癌的潜在治疗标和生物标志物.
这项研究强调了使用新型SERM和SERD治疗内分泌耐药ER+乳腺癌的新疗法.

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