Small Molecule Inhibitors that Disrupt the MTDH-SND1 Complex Suppress Breast Cancer Progression and Metastasis. Small Molecule Inhibitors that Disrupt the MTDH-SND1 Complex Suppress Breast Cancer Progression and Metastasis

Previous studies discovered that MTDH frequently amplifies and overexpresses in breast cancer in human patients and is strongly associated with higher metastasis and treatment failure and thereby leads to poor prognosis. In mouse mammary tumor models, knockout of Mtdh substantially reduces tumor incidence and suppresess metastasis. Furthermore, Mtdh interact with Snd1 and the interaction appears essential for its tumor promoting function. To develop novel therapeutics targeting Mtdh function, small molecular compound to disrupt the Mtdh-Snd1 interaction was identified by high throughput screen. To further elucidate the mechanism of MTDH targeting caused anti-tumor activity and to confirm the action mode of the small molecular compound C26A6 as a Mtdh-Snd1 disruptor, transcriptome changes in mouse mammary tumors following treatments of C26A6 and acute induction of Mtdh knockout by Tamoxifen treatment were investigated using next generation sequencing. Overall design: MTDH targeting induced mammary tumor transcriptome changes were determined by RNAseq profiling. 3 treatment groups of C26A6, Tamoxifen and vehicle control (corn oil+saline) (n=4 each group) were tested.

既往研究表明，MTDH在人类乳腺癌患者中常发生扩增与过表达，且与更高的转移风险、治疗失败风险显著相关，进而导致不良预后。
在小鼠乳腺肿瘤模型中，敲除Mtdh可显著降低肿瘤发生率并抑制肿瘤转移。
此外，Mtdh可与Snd1发生相互作用，且该相互作用对其促肿瘤功能至关重要。
为开发靶向MTDH功能的新型治疗手段，研究人员通过高通量筛选（high-throughput screening）获得了可破坏Mtdh-Snd1相互作用的小分子化合物。
为进一步阐明靶向MTDH介导的抗肿瘤活性的机制，并验证小分子化合物C26A6作为Mtdh-Snd1相互作用抑制剂的作用模式，研究人员采用下一代测序（next-generation sequencing）技术，对经C26A6处理、他莫昔芬（Tamoxifen）诱导Mtdh急性敲除的小鼠乳腺肿瘤的转录组变化进行了分析。
实验整体设计：通过RNA测序（RNAseq）分析靶向MTDH诱导的小鼠乳腺肿瘤转录组变化。本实验设置C26A6处理组、他莫昔芬处理组与溶媒对照组（玉米油+生理盐水）共3组，每组n=4。