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

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
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.


EGFR (Epidermal Growth Factor Receptor)
Hatil, Ayca Circir; Çiçek, Esra; Öyken, Merve; Erson Bensan, Ayşe Elif (2020-01-01)
© 2020 Atlas of Genetics and Cytogenetics in Oncology and Haematology.ERBB family member epidermal receptor tyrosine kinase (EGFR) is composed of 28 exons and 27 introns. EGFR codes for 11 transcripts and 8 of them are protein coding. EGFR is a transmembrane glycoprotein that can be activated by several different ligands such as epidermal growth factor (EGF), transforming growth factor-alpha (TGFA), heparin-binding EGF-like growth factor (HBEGF), betacellulin (BTC), amphiregulin (AREG), epiregulin (EREG), a...
Regulation and role of CCAAT/enhancer binding protein during differentiation of intestinal epithelial cells
Memişoğlu, Aslı Sade; Banerjee, Sreeparna (2013-09-01)
Background: The molecular mechanisms of differentiation of intestinal epithelial cells, is poorly understood and disruption of this balance may result in neoplastic transformation and malignant growth. The family of CCAAT/Enhancer Binding Protein (C/EBP) transcription factors is implicated in cellular growth, differentiation, inflammation and development and control differentiation in several cell types. The involvement of these transcription factors in intestinal differentiation is not known. The aim of th...
Systemic Delivery of Bioactive Glucagon-Like Peptide 1 after Adenoviral-Mediated Gene Transfer in the Murine Salivary Gland
Voutetakis, Antonis; Cotrim, Ana P.; Rowzee, Anne; Zheng, Changyu; Rathod, Trushar; Yanık, Tülin; Loh, Y. Peng; Baum, Bruce J.; Cawley, Niamh X. (2010-09-01)
Anadenoviral (Ad) vector that expresses bioactive glucagon-like peptide 1 (GLP-1) was generated, and its effectiveness at modulating glucose homeostasis was evaluated after transduction of murine salivary glands. The construct was engineered with the signal sequence of mouse GH to direct the peptide into the secretory pathway, followed by a furin cleavage site and the GLP-1(7-37) sequence encoding an Ala to Gly substitution at position 8 to achieve resistance to degradation. When expressed in Neuro2A and CO...
Evaluation of neointimal hyperplasia on tranilast-coated synthetic vascular grafts: An experimental study
Karakayali, Feza; Haberal, Nihan; Tufan, Hale; Hasırcı, Nesrin; BaSaran, Ozgur; Sevmis, Sinasi; Akdur, Aydin; Kızıltay, Aysel; Haberal, Mehmet (2007-01-01)
Tranilast is an antiallergic drug that interferes with proliferation and migration of vascular smooth muscle cell induced by platelet-derived growth factor (PDGF) and transforming growth factor-beta 1 (TGF-beta 1). We investigated the local effect of tranilast on neointimal hyperplasia using tranilastcoated prosthetic grafts. The inner sides of the thin-walled polytetrafluoroethylene (PTFE) grafts were coated with chitosan and tranilast containing chitosan solution. Wistar albino rats (32) were used in the ...
Evaluation of methylation profiles of an epidermal growth factor receptor gene in a head and neck squamous cell carcinoma patient group
Mutlu, M.; Mutlu, Pelin; Azarkan, S.; Baylr, Ö.; Öcal, B.; Saylam, G.; KORKMAZ, MEHMET HAKAN (2021-03-23)
Upregulation of the epidermal growth factor receptor (EGFR) gene has shown an important impact on the development of head and neck cancers due to its important regulation role on multiple cell signaling pathways. The aim of this study was to investigate the methylation pattern of the promoter region of the EGFR gene between head and neck squamous cell carcinoma (HNSCC) patients and a control group. Forty-seven unrelated HNSCC patients, clinically diagnosed at the Department of Otorhinolaryngology, Dlşkapl Y...
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: