IRAK2 contributes to triple-negative breast cancer growth via NF-κB, ERK and stress-related signaling pathways

Abstract

PurposeWe previously screened kinases whose depletion elicited a differentiation response of the triple-negative breast cancer (TNBC) cell line MDA-MB-468. In particular, we demonstrated that the downregulation of the kinases ERN1 and ALPK1 affected cellular proliferation, self-renewal and tumor-forming capacity. Interleukin-1 receptor-associated kinase 2 (IRAK2) was identified in the screening and IRAK2 is highly enriched in our established breast cancer stem cells (BCSCs) isolated from human tumors of TNBC. Therefore, we wondered if IRAK2 depletion could affect BCSCs growth. MethodsWe downregulated IRAK2 in BCSCs and MDA-MB-468 by lentivirus-mediated shRNA targeting and assessed the effects of the knockdown evaluating keratins expression, cellular proliferation and self-renewal capacity. We injected the cells into the mammary glands of mice to evaluate the impact of IRAK2 knockdown on their tumor-forming capacity. We investigated the expression of genes belonging to IRAK2 pathway and related to cancer proliferation, UPR, autophagy and apoptosis in presence of IRAK2 downregulation. We performed transcriptome analysis to have an overview of the pathways affected by the knockdown. Results Cells characterized by IRAK2 downregulation exhibited decreased proliferation, sphere-forming capacity and delayed tumor formation. IRAK2 knockdown impaired NF-κB and ERK phosphorylation, IL-6 and cyclin D1 expression. Moreover, IRAK2 downregulation mitigated ERN1 signalling and autophagy, pathways adopted by cells to manage stress conditions, and induced apoptosis.ConclusionWe showed that IRAK2 contributes to TNBC tumorigenicity and its knockdown compromises cellular ability to sustain aggressive growth and to endure cellular stress. Therefore we suggest IRAK2 as a promising target for the impairment of TNBC.