SNX3 LOSS ENHANCES EGFR OVEREXPRESSION IN A MOUSE TRIPLE NEGATIVE BREAST CANCER MODEL

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2023-1-23

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Çırçır, Ayça

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Sorting nexin 3 (SNX3) is one of the sorting nexin family proteins and recruits the retromer complex in endosomal trafficking. SNX3 binds specifically to Phosphotidylinositol3Phosphate (PtdIns(3)P) via its Phox-domain (PX) domain but can also interact with cargo proteins which are mostly membrane receptors. Internalized receptors can be recycled back to the plasma membrane or the trans Golgi network or degraded in lysosomes or proteosomes. In addition to the role of SNX3 in Wntless (Wls) and Transferrin receptor (Tfrc) turnover, previous work and ours demonstrated the epidermal growth factor receptor (EGFR) as a recycling cargo of SNX3. Considering the critical role of EGFR in cell survival, proliferation, invasion/migration and clonogenicity of EGFR positive triple negative breast cancers (TNBCs), we hypothesized that SNX3 might modulate EGFR levels in TNBCs and deregulation of SNX3 might result in the alteration of clinical phenotypes. To experiment with our hypothesis, we generated Snx3 knockdown mouse mammary cell line models and evaluated the alterations in the neoplastic phenotypes of the cells. Early response to Snx3 downregulation decreased the Egfr protein, whereas extended silencing of Snx3 resulted in both Egfr protein and Egfr mRNA upregulation. Upregulation of the Egfr protein enhanced the phenotype of 4T1 cells to a more aggressive state. In summary, Snx3 levels are critical for Egfr protein levels. Our results suggest that Snx3 loss may explain Egfr overexpression cases in triple negative breast cancer patients who do not have genomic amplification.

Subject Keywords

Sorting nexin 3, Epidermal growth factor receptor, Triple negative breast cancer, Phenotypic assay

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https://hdl.handle.net/11511/102067

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Graduate School of Natural and Applied Sciences, Thesis

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Citation Formats

A. Çırçır, “SNX3 LOSS ENHANCES EGFR OVEREXPRESSION IN A MOUSE TRIPLE NEGATIVE BREAST CANCER MODEL,” Ph.D. - Doctoral Program, Middle East Technical University, 2023.