Abstract 1233: WNT inhibitor ICG-001 prevents visceral metastatic triple negative breast cancer in a chemo-resistant patient derived xenograft -PDX-model

Triple negative breast cancer (TNBC) is characterized by absence of the estrogen receptor (ER) and progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2) amplification. Such cancers are highly aggressive and frequently metastasize to the lung and brain. Unlike other breast cancer subtypes such as, ER+, PR+ and/or HER2+, TNBCs have no specific targeted-therapeutics; therefore, studies should be directed for development of targeted therapies to treat this condition. Recent studies indicate that Wnt/β-catenin signaling is particularly activated in TNBC and is associated with reduced overall survival in all patients. Therefore, pharmacological targeting of Wnt signaling pathway constitutes an ideal approach for treating TNBC and various Wnt inhibitors are currently in use in clinical trials, such as; ICG-001 in metastatic colon cancer. The inhibitory effects of ICG-001 have not been tested in chemoresistant TNBC PDX tumors. Herein, we report for the first time that ICG-001 compound selectively inhibited the growth of several European American (EA) and African American (AA) triple negative breast cancer subtypes MSL and BSL-1 cell lines both in vitro and in vivo models. To further investigate the precise mechanisms of action in the regulation of Wnt/β-catenin signaling by ICG-001, we performed Western blot analysis, apoptosis assays, cell cycle assays and quantitative real-time reverse transcriptase- polymerase chain reactions in human triple negative breast cancer cells. This compound significantly interfered with Wnt/β-catenin signaling, and its inhibition led to downregulation of important downstream targets such as Axin2, HMGA2, PCNA, c-myc and Cyclin D1, which in turn led to inhibition of proliferation, cell cycle progression and metastasis confirming our previous results too. In addition ICG-001 inhibited the invasion and motility of tumor cells and showed inhibition and prevention of visceral metastatic PDX tumors from both chemoresistant EA and AA women. These results indicate that the Wnt inhibitor ICG-001 could constitute a powerful new chemotherapeutic agent against triple negative breast cancer. Citation Format: Iram Fatima, Ikbale El Ayachi, Chidi Zacheaus, Joseph Kerby Gray, Raya Krutilina, Tiffany N. Seagroves, Susan A. Krum, Gustavo A. Miranda-Carboni. WNT inhibitor ICG-001 prevents visceral metastatic triple negative breast cancer in a chemo-resistant patient derived xenograft -PDX-model [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1233. doi:10.1158/1538-7445.AM2017-1233