EGF-SNX3-EGFR axis drives tumor progression and metastasis in triple-negative breast cancers

Sorting Nexin 3 (SNX3), a member of the recycling retromer complex, is a critical player in the epidermal growth factor (EGF) stimulated EGFR network in triple-negative breast cancers.

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Overexpression of EGFR and its association with poor prognosis are known in many cancers, including breast cancer. However, EGFR gene amplification or mutations can only partly explain EGFR overexpression cases.

In this recent paper, we describe Sorting Nexin 3 (SNX3), a member of the recycling retromer complex, as a critical player in the epidermal growth factor (EGF) stimulated EGFR network in triple-negative breast cancer (TNBC). We show that SNX3 is an immediate and sustained target of EGF stimulation initially at the protein level and later at the transcriptional level, causing increased SNX3 protein levels. In turn, SNX3 and EGFR interaction increases while SNX3 co-localizes with early endosomes and endocytosed EGF.

Interestingly, EGFR protein levels are highly sensitive to SNX3 loss. Transient RNAi models of SNX3 downregulation temporarily reduce EGFR levels due to decreased recycling of EGFR. In contrast, long-term silencing forces cells to recover and overexpress EGFR mRNA and protein, resulting in increased proliferation, colony formation, migration, invasion in TNBC cells, and increased tumor growth and metastasis in syngeneic models. In breast cancer patients, low SNX3 and high EGFR mRNA levels correlate with poor relapse-free survival.

Overall, these results show that SNX3 is a target of the EGF-induced EGFR pathway and that loss of SNX3 function leads to EGFR overexpression in TNBCs. Hence, the EGF-SNX3-EGFR axis we describe may have implications for developing potent therapies targeting the EGFR network and possibly understanding resistance mechanisms to anti-EGFR therapies not only in TNBCs but also in other malignancies dependent on EGFR activity.

A SNX3 protein levels are upregulated during the early response to EGF stimulation. Prolonged exposure to EGF causes transcriptional upregulation. In turn, SNX3, as a retromer protein, interacts with EGFR and endocytosed EGF in early endosomes. B Sustained silencing of SNX3 causes EGFR mRNA and protein upregulation, causing increased neoplastic phenotypes in vitro and in vivo. In support of these, TNBC patients with low SNX3 and high EGFR mRNA have poor overall survival.

Elif Erson-Bensan, PhD

PI, Orta Doğu Teknik Üniversitesi (ODTÜ) Department of Biological Sciences Middle East Technical University (METU)