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. 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.