FUNCTIONAL AND EXPRESSION ANALYSIS OF INTERFERON-INDUCED PROTEIN WITH TETRATRICOPEPTIDE REPEATS (IFIT) IN BREAST CANCER

Abstract

Breast cancer is one of the most common cancers in women, and metastasis is the primary cause of death. Interferon-induced protein with tetratricopeptide repeats proteins (IFITs) participate in antiviral defence under the regulation of interferon. Previous studies on breast cancer showed that IFIT1 increased cancer cell migration and invasion and correlated with higher patient mortality rate. However, the functional roles of IFIT2 and IFIT3 in breast malignancy are largely unknown. To address this knowledge gap, experiments were conducted by generating IFIT2,3-overexpressing human breast cancer cells or reducing IFIT2,3 expression using siRNA or CRISPR-Cas9. In vitro and in vivo experiments suggested that all three IFITs enhanced breast cancer cell aggressiveness. Additionally, IFIT3 stabilised the expression of IFIT1 and IFIT2, blocked lysosomal degradation of EGFR, and enhanced the activation of EGFR downstream signaling molecules (AKT, JNK, STAT3 and CREB). Immunohistochemical analysis of invasive ductal carcinoma patient samples suggested that high IFIT3 expression correlated with higher cancer grade and cause-specific mortality rate. Greater expression of IFIT2 was associated with increased lymph node metastasis and mortality rate. Taken together, the data showed that IFIT2 and IFIT3 promoted the aggressiveness of breast cancer cells and could be used to refine prognostication of cancer patients.