TNFAIP3 promotes ALDH-positive breast cancer stem cells through FGFR1/MEK/ERK pathway.

Abstract

Breast cancer stem cells (BCSCs) are a tiny population of self-renewing cells that may contribute to cancer initiation, progression, and resistance to therapy in patients. In our prior study, we found that tumor necrosis factor alpha-induced protein 3 (TNFAIP3) is necessary for fibroblast growth factors receptor 1 (FGFR1) signaling-promoted tumor growth and progression in breast cancer (BC). This study aims to investigate the involvement of TNFAIP3 in regulating BCSCs. In this work, we showed that ALDH-positive BCSCs were increased by activating the FGFR1-MEK-ERK pathway, meanwhile utilizing FGFR1 inhibitor, MEK inhibitor, or ERK inhibitor reversed the phenomenon in BC cells. Moreover, ALDH-positive BCSCs were decreased in TNFAIP3-knockout or TNFAIP3-depressing cells. In vivo analysis displayed that TNFAIP3-silenced MDA-MB-231 xenografts developed smaller tumors and ALDH immunostaining levels were significantly lower in TNFAIP3-depressing or TNFAIP3-knockout tumor tissues. Besides, our results also revealed that TNFAIP3 influences the transcription stemness factors gene expression. Taken together, TNFAIP3 could be a potential regulator in FGFR1-MEK-ERK-promoted ALDH-positive BCSCs.