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

Date

2021-10-30

Author

Cicek, Esra
Circir, Ayca
Oyken, Merve
Akbulut Caliskan, Ozge
Dioken, Didem Naz
Guntekin Ergun, Sezen
Cetin-Atalay, Rengul
Sapmaz, Aysegul
Ovaa, Huib
Sahin, Ozgur
Erson Bensan, Ayşe Elif

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Epidermal growth factor receptor (EGFR) has critical roles in epithelial cell physiology. Over-expression and over-activation of EGFR have been implicated in diverse cancers, including triple-negative breast cancers (TNBCs), prompting anti‐EGFR therapies. Therefore, developing potent therapies and addressing the inevitable drug resistance mechanisms necessitates deciphering of EGFR related networks. Here, 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 TNBCs. 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 abundance. Using a proximity labeling approach, we observed increased interaction of SNX3 and EGFR upon EGF stimulation. We also detected colocalization of SNX3 with early endosomes and endocytosed EGF. Moreover, we show that EGFR protein levels are sensitive to SNX3 loss. Transient RNAi models of SNX3 downregulation have a temporary reduction in EGFR levels. 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. Consistent with these results, low SNX3 and high EGFR mRNA levels correlate with poor relapse-free survival in breast cancer patients. Overall, our results suggest that SNX3 is a critical player in the EGFR network in TNBCs with implications for other cancers dependent on EGFR activity.

URI

https://hdl.handle.net/11511/94279

Journal

Oncogene

DOI

https://doi.org/10.1038/s41388-021-02086-9

Collections

Department of Biology, Article

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Citation Formats

E. Cicek et al., “EGF-SNX3-EGFR axis drives tumor progression and metastasis in triple-negative breast cancers.,” Oncogene, 2021, Accessed: 00, 2021. [Online]. Available: https://hdl.handle.net/11511/94279.