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Monomeric EGFR-mediated activation of STAT3 promotes triple-negative breast cancer progression

ABSTRACT: Dimerization is believed necessary for receptor tyrosine kinases (RTKs) activation. Here we report that monomeric epidermal growth factor receptor (EGFR) directly phosphorylates the signal transducer and activator of transcription-3 (STAT3) in the absence of transmembrane protein TMEM25 (hereafter referred to as TAMER (Transmembrane protein Antagonizing Monomeric EGF Receptor signaling) to reflect its molecular function). We identified TAMER as a checkpoint for the monomeric-EGFR/STAT3 signaling, and downregulation of TAMER in triple-negative breast cancer (TNBC) results in a persistent activation of STAT3 that is required for TNBC progression, which gives a good explanation why targeting EGFR dimerization by antibodies showed no significant benefit to TNBC patients in clinical trials. Remarkably, supply of TAMER strongly suppressed TNBC progression, presenting a promising targeted therapy for TNBC. Hence, our study demonstrated the first RTK monomer-mediated signaling pathway, introducing an unprecedented pattern of RTK signaling that may play key roles in certain physiological or pathological contexts, which might need to be inspected for therapeutically targeting RTKs in the future.In this paper, RNA-seq were used to identify different gene expression in WT and TMEM25 knockout MDA-MB-231 cells.

ORGANISM(S): Homo sapiens

PROVIDER: GSE180989 | GEO | 2024/07/28

REPOSITORIES: GEO

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