Disrupting interferon-alpha and NF-kappaB crosstalk suppresses IFITM1 expression attenuating triple-negative breast cancer progression
| Autor: | Eric S. Geanes, Sean M. Holloran, Anuradha Roy, Olivia K. Provance, Sumedha Gunewardena, Christy R. Hagan, Scott Weir, Asona Lui, Joan Lewis-Wambi |
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| Rok vydání: | 2021 |
| Předmět: |
Adult
0301 basic medicine Cancer Research Down-Regulation Alpha interferon Triple Negative Breast Neoplasms Biology Article Mice 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine Downregulation and upregulation Cell Movement In vivo Interferon Cell Line Tumor medicine Animals Humans Parthenolide Triple-negative breast cancer Aged Cell Proliferation Tissue microarray NF-kappa B Interferon-alpha Middle Aged Antigens Differentiation Gene Expression Regulation Neoplastic 030104 developmental biology Oncology chemistry Tumor progression 030220 oncology & carcinogenesis Cancer research Female Signal Transduction medicine.drug |
| Zdroj: | Cancer Lett |
| ISSN: | 0304-3835 |
| DOI: | 10.1016/j.canlet.2021.05.006 |
| Popis: | Overexpression of interferon induced transmembrane protein-1 (IFITM1) enhances tumor progression in multiple cancers, but its role in triple-negative breast cancer (TNBC) is unknown. Here, we explore the functional significance and regulation of IFITM1 in TNBC and strategies to target its expression. Immunohistochemistry staining of a tissue microarray demonstrates that IFITM1 is overexpressed in TNBC samples which is confirmed by TCGA analysis. Targeting IFITM1 by siRNA or CRISPR/Cas9 in TNBC cell lines significantly inhibits proliferation, colony formation, and wound healing in vitro. Orthotopic mammary fat pad and mammary intraductal studies reveal that loss of IFITM1 reduces TNBC tumor growth and invasion in vivo. RNA-seq analysis of IFITM1/KO cells reveals significant downregulation of several genes involved in proliferation, migration, and invasion and functional studies identified NF-κB as an important downstream target of IFITM1. Notably, siRNA knockdown of p65 reduces IFITM1 expression and a drug-repurposing screen of FDA approved compounds identified parthenolide, an NFκB inhibitor, as a cytotoxic agent for TNBC and an inhibitor of IFITM1 in vitro and in vivo. Overall, our findings suggest that targeting IFITM1 by suppressing interferon-alpha/NFκB signaling represents a novel therapeutic strategy for TNBC treatment. |
| Databáze: | OpenAIRE |
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