Abstract 1899: Targeting interferon induced transmembrane protein-1 (IFITM1) attenuates the aggressive phenotype of inflammatory breast cancer

Abstract

Abstract Inflammatory breast cancer (IBC) is the most aggressive and lethal subtype of breast cancer, with triple-negative IBC being the most difficult to treat IBC subgroup. Improved understanding of mechanisms that lead to aggressiveness of triple-negative IBC could provide a basis for therapeutic targets. Our laboratory has identified a novel interferon (IFN)-α signaling target called interferon induced transmembrane protein-1 (IFITM1), which we hypothesize to promote the aggressive phenotype of triple-negative IBC. CRISPR/CAS9 was utilized to silence IFITM1 in SUM149 TN-IBC cells. In vitro, we found that knockout of IFITM1 increased in colony and mammosphere formation, inhibited migration as observed by the wound healing assay, and enhanced sensitivity to mainstay chemotherapeutic agents (taxol and doxorubicin) analyzed by flow cytometry, MTT and Tunel staining. Western blot analysis shows a decrease in c-Src and p-Src, vimentin, and CD44v expression, which are important regulators of migration and invasion. RNA sequencing analysis further indicates that knocking down IFITM1 promotes overall downregulation of pathways including breast cancer invasion, supporting our in vitro findings. In vivo, IFITM1-CRISPR/KD SUM149 cells were injected into the mammary fat pads of immunosuppressed female NSG mice to assess tumor growth. We found that mice injected with IFITM1-CRISPR/KD SUM149 cells showed significantly reduced tumor growth compared to mice injected with CRISPR/control SUM149 cells, which was observed at all time points examined. We used the mammary intraductal (MIND) method to assess tumor invasion in vivo. IFITM1-CRISPR/KD SUM149 cells showed decreased invasion outside of the mammary duct and decreased vimentin expression, further corroborating our in vitro data. Lastly, through tail vein injections to model metastasis, 33% of mice injected with SUM149 wildtype cells developed liver metastasis while 0% of mice injected with IFITM1-CRISPR/KD SUM149 mice developed liver metastasis. We have ongoing studies to further understand the mechanism by which IFITM1 regulates cellular migration, as well as invasion and angiogenesis in triple-negative IBC, which are all shown to be downregulated through RNA sequencing analysis. Overall, these findings indicate that IFITM1 may be driving the aggressiveness of triple-negative IBC and they suggest that IFITM1 may serve as a potential therapeutic target. Citation Format: Olivia Provance, Eric Geanes, Joshua Ogony, Asona Lui, Eric Young, Sumedha Gunewardena, Joan Lewis-Wambi. Targeting interferon induced transmembrane protein-1 (IFITM1) attenuates the aggressive phenotype of inflammatory breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1899.