PO.ET04.01 · 实验与分子治疗
一种通过过表达突变型雌激素受体治疗乳腺癌的新型基因治疗策略
A novel gene therapy approach for treating breast cancer through the overexpression of mutant estrogen receptor
作者与单位 Authors & Affiliations
摘要 Abstract
中文摘要
背景：内分泌治疗（ET）是激素受体阳性（HR+）乳腺癌的主要治疗手段，但耐药性不可避免地会出现，导致内分泌耐药性乳腺癌。尽管他莫昔芬和芳香化酶抑制剂等药物可改善预后，耐药机制仍是重大挑战。这提示雌激素受体（ER）信号通路具有复杂的作用。我们假设维持一种无功能的突变型ER（mER）能够克服这种耐药性。
方法：我们合成了一个在DNA结合结构域（DBD）中带有突变的全长ER（ESR1）基因。为确保靶向递送，将编码mER的质粒包裹于聚（乳酸-羟基乙酸）共聚物（PLGA）纳米颗粒中。这些纳米颗粒表面修饰了ER配体4-羧基-17β-雌二醇，以促进对ER阳性乳腺癌细胞的主动靶向。在体外采用HER2-ER+PR+的MCF7和T47D细胞系及其他莫昔芬耐药（TamR）对应细胞系研究了mER过表达的效应。采用异种移植小鼠模型评估了体内抗肿瘤效应。
结果：ER靶向PLGA纳米颗粒在体外和体内均有效地将mER质粒递送至表达ER的乳腺癌细胞。mER的过表达未激活雌激素反应性基因，并在MCF7和T47D细胞中均发挥了强效的抗增殖作用。值得注意的是，mER过表达在他莫昔芬耐药（TamR）的MCF7和T47D细胞中仍保持其强效抗肿瘤活性。机制上，mER过表达导致野生型ER（wtER）水平降低，并抑制了DNA复制相关的基因通路。在体内，mER治疗显著抑制了标准型和他莫昔芬耐药型肿瘤的生长。此外，当mER与他莫昔芬联合使用时观察到协同抗肿瘤效应。
结论：通过ER靶向纳米颗粒系统递送的、带有无功能DBD的突变型ER的过表达，代表了一种针对晚期HR+乳腺癌（包括内分泌耐药和他莫昔芬耐药疾病）的新型治疗策略。通过抑制wtER、破坏DNA复制并在耐药模型中维持活性，mER有效抑制肿瘤生长并克服治疗耐药性。
查看英文原文 English abstract
Background: Endocrine therapy (ET) is the primary treatment for hormone receptor-positive (HR+) breast cancer, but resistance inevitably develops, leading to endocrine-resistant breast cancer. While agents like tamoxifen and aromatase inhibitors improve outcomes, resistance mechanisms remain significant challenges. This suggests a complex role for estrogen receptor (ER) signaling. We hypothesized that maintaining a non-functional, mutant ER (mER) could overcome this resistance.
Methods: We synthesized a full-length ER (ESR1) gene with a mutation in the DNA-binding domain (DBD). To ensure targeted delivery, the mER-encoding plasmid was encapsulated within poly(lactic-co-glycolic acid) (PLGA) nanoparticles. These nanoparticles were surface-functionalized with 4-carboxyl-17beta-estradiol, an ER ligand, to facilitate active targeting to ER-positive breast cancer cells. The effects of mER overexpression were investigated in vitro using HER2-ER+PR+ MCF7 and T47D cell lines, as well as their tamoxifen-resistant (TamR) counterparts. In vivo antitumoral effects were assessed using xenograft mouse models.
Results: The ER-targeted PLGA nanoparticles effectively delivered the mER plasmid to ER-expressing breast cancer cells in vitro and in vivo. Overexpression of mER did not activate estrogen-responsive genes and exerted a potent antiproliferative effect in both MCF7 and T47D cells. Notably, mER overexpression maintained its strong antitumoral activity in tamoxifen-resistant (TamR) MCF7 and T47D cells. Mechanistically, mER overexpression led to a reduction in wild-type ER (wtER) levels and suppressed DNA replication-related gene pathways. In vivo, mER treatment significantly inhibited the growth of both standard and tamoxifen-resistant tumors. Furthermore, a synergistic antitumoral effect was observed when mER was combined with tamoxifen.
Conclusions: Overexpression of a mutant ER with a non-functional DBD, delivered via an ER-targeted nanoparticle system, represents a novel therapeutic strategy for advanced HR+ breast cancer, including endocrine-resistant and tamoxifen-resistant disease. By suppressing wtER, disrupting DNA replication, and maintaining activity in resistant models, mER effectively inhibits tumor growth and overcomes therapeutic resistance.
利益披露 Disclosure
S. Jeong,
Adrian and Eden Employment, Other Business Ownership, ).