文章：

人源化RANKL转基因小鼠模型用于评估新型治疗药物对孕激素诱导乳腺癌发生的作用

Α Humanized RANKL Transgenic Mouse Model of Progestin-Induced Mammary Carcinogenesis for Evaluation of Novel Therapeutics

原文发布日期：7 August 2023

DOI: 10.3390/cancers15154006

类型: Article

开放获取: 是

英文摘要：

Receptor activator of nuclear factor-κB ligand (RANKL) is critically involved in mammary gland pathophysiology, while its pharmaceutical inhibition is being currently investigated in breast cancer. Herein, we investigated whether the overexpression of human RANKL in transgenic mice affects hormone-induced mammary carcinogenesis, and evaluated the efficacy of anti-RANKL treatments, such as OPG-Fc targeting both human and mouse RANKL or Denosumab against human RANKL. We established novel MPA/DMBA-driven mammary carcinogenesis models in TgRANKL mice that express both human and mouse RANKL, as well as in humanized humTgRANKL mice expressing only human RANKL, and compared them to MPA/DMBA-treated wild-type (WT) mice. Our results show that TgRANKL and WT mice have similar levels of susceptibility to mammary carcinogenesis, while OPG-Fc treatment restored mammary ductal density, and prevented ductal branching and the formation of neoplastic foci in both genotypes. humTgRANKL mice also developed MPA/DMBA-induced tumors with similar incidence and burden to those of WT and TgRANKL mice. The prophylactic treatment of humTgRANKL mice with Denosumab significantly prevented the rate of appearance of mammary tumors from 86.7% to 15.4% and the early stages of carcinogenesis, whereas therapeutic treatment did not lead to any significant attenuation of tumor incidence or tumor burden compared to control mice, suggesting the importance of RANKL primarily in the initial stages of tumorigenesis. Overall, we provide unique genetic tools for investigating the involvement of RANKL in breast carcinogenesis, and allow the preclinical evaluation of novel therapeutics that target hormone-related breast cancers.

摘要翻译： 

核因子-κB配体受体激活剂（RANKL）在乳腺病理生理学中起关键作用，目前其药物抑制效应已在乳腺癌研究中展开探索。本研究探讨了转基因小鼠中人类RANKL的过表达是否影响激素诱导的乳腺致癌过程，并评估了抗RANKL疗法的效果——包括针对人类与小鼠RANKL的双靶向药物OPG-Fc以及特异性针对人类RANKL的狄诺塞麦。我们在同时表达人类和小鼠RANKL的TgRANKL转基因小鼠、以及仅表达人类RANKL的人源化humTgRANKL小鼠中，建立了新型MPA/DMBA驱动的乳腺致癌模型，并与MPA/DMBA处理的野生型（WT）小鼠进行对比。结果表明：TgRANKL与WT小鼠对乳腺致癌的易感性水平相近，而OPG-Fc治疗能恢复乳腺导管密度，并在两种基因型中均抑制导管分支形成及肿瘤灶发育。humTgRANKL小鼠同样出现MPA/DMBA诱导的肿瘤，其发生率和负荷与WT及TgRANKL小鼠相当。狄诺塞麦预防性治疗将humTgRANKL小鼠的乳腺肿瘤发生率从86.7%显著降低至15.4%，并抑制了癌变的早期进程；而治疗性干预相比对照组未显著降低肿瘤发生率或负荷，这提示RANKL主要在肿瘤发生的起始阶段发挥重要作用。本研究为探索RANKL在乳腺癌发生中的参与机制提供了独特的遗传学工具，并为靶向激素相关性乳腺癌的新型疗法临床前评估建立了实验平台。

原文链接：

Α Humanized RANKL Transgenic Mouse Model of Progestin-Induced Mammary Carcinogenesis for Evaluation of Novel Therapeutics