Abstract 3560: IFITM1 overexpression enhances the aggressive phenotype of inflammatory breast cancer in a STAT2-dependent manner
Authors: Ogony Joshua Were , Lewis-Wambi Joan 
Published: August 2015

Inflammatory breast cancer (IBC) is a highly metastatic, aggressive, and fatal form of breast cancer that accounts for about 1 to 5% of all breast cancers diagnosed in the United States. At present, the molecular mechanisms that underlie the aggressive phenotype of IBC are not known. Interferon induced transmembrane protein1 (IFITM1) is a member of interferon stimulated genes (ISGs), whose overexpression has been linked to several malignancies, but its role in inflammatory breast cancer is not known. The primary role of IFITM1 is to stop the spread of viral pathogens in the host's cells, but its constitutive overexpression has been shown to enhance malignancy. IFITM1 expression is known to be regulated by type 1 interferon through activation of the canonical JAK-STAT pathway; however, recent studies suggest that non-canonical signaling pathways involving STAT2 homodimers can also regulate IFITM1 expression. In the present study, we determined whether IFITM1 plays a critical role in driving the aggressive phenotype of three IBC cell lines; SUM149; MDA-IBC-3, and SUM190.

Western blot and RT-PCR analyses indicated that IFITM1 was constitutively overexpressed at the protein (∼5- to 10-fold) and mRNA (∼4-fold) level, respectively, in SUM149 and MDA-IBC-3 cells but not expressed in non-IBC MCF-7 luminal breast cancer cells, and that its overexpression strongly correlated with increased proliferation, migration and invasion, and enhanced colony formation.

Notably, the aggressive phenotype of SUM149 and MDA-IBC-3 cells was completely reversed by siRNA knockdown of IFITM1. Specifically, we found that suppression of IFITM1 significantly reduced the ability of SUM149 and MDA-IBC-3 cells to proliferate, migrate and invade, and form colonies. Furthermore, we found that IFITM1 expression and promoter activity were completely abolished due to STAT2 knockdown and that BRG1 (Brahma-related-gene 1) was crucial for the expression of IFITM1 and STAT2 in the IBC cells.

Moreover, we found that knockdown of BRG1; a member of the mammalian chromatin-remodeling complex markedly reduced IFITM1 and STAT2 proteins, but not STAT1, in SUM149 and MDA-IBC-3 cells, thus supporting a critical role for STAT2/BRG1 in the regulation of IFITM1 expression in these cells. Taken together, this data suggests that constitutive overexpression of IFITM1 in inflammatory breast cancer cells enhances the aggressive phenotype of these cells, and that STAT2 and BRG1 play pivotal roles in driving IFITM1 overexpression.

Additionally, this data suggests that IFITM1 may be a suitable candidate as a novel therapeutic target and a potential prognostic maker for inflammatory breast cancer.

Citation Format: Joshua Were Ogony, Joan Lewis-Wambi. IFITM1 overexpression enhances the aggressive phenotype of inflammatory breast cancer in a STAT2-dependent manner. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3560. doi:10.1158/1538-7445.AM2015-3560