SCAMP3 Regulates EGFR and Promotes Proliferation and Migration of Triple-Negative Breast Cancer Cells through the Modulation of AKT, ERK, and STAT3 Signaling Pathways.

Abstract

Simple SummaryTriple-negative breast cancer (TNBC) cases constitute ~15% of breast cancer tumors. This subtype is characterized by the lack of hormone receptors, estrogen and progesterone, and HER2, and it is a more aggressive, metastatic, and recurrent subtype than others. The need to develop novel anti-TNBC drugs encourages scientists to direct studies to identify potential therapeutic molecular targets. Our study aimed to define the role of the secretory carrier membrane protein, SCAMP3, in TNBC, and its association with the epidermal growth factor receptor (EGFR), which is present in ~90% of tumors. We confirmed that SCAMP3 promotes cell proliferation and motility and is directly associated with EGFR redistribution and degradation. It also regulates the gene and protein expression of molecules from the EGFR and PDGFR pathways. Finally, SCAMP3 depletion delays the establishment of TNBC tumors. This study provides evidence for SCAMP3′s TNBC tumor-promoting role and its potential as a target therapy for this disease.Triple-negative breast cancer (TNBC) is the most aggressive, metastatic, and lethal breast cancer subtype. To improve the survival of TNBC patients, it is essential to explore new signaling pathways for the further development of effective drugs. This study aims to investigate the role of the secretory carrier membrane protein 3 (SCAMP3) in TNBC and its association with the epidermal growth factor receptor (EGFR). Through an internalization assay, we demonstrated that SCAMP3 colocalizes and redistributes EGFR from the cytoplasm to the perinucleus. Furthermore, SCAMP3 knockout decreased proliferation, colony and tumorsphere formation, cell migration, and invasion of TNBC cells. Immunoblots and degradation assays showed that SCAMP3 regulates EGFR through its degradation. In addition, SCAMP3 modulates AKT, ERK, and STAT3 signaling pathways. TNBC xenograft models showed that SCAMP3 depletion delayed tumor cell proliferation at the beginning of tumor development and modulated the expression of genes from the PDGF pathway. Additionally, analysis of TCGA data revealed elevated SCAMP3 expression in breast cancer tumors. Finally, patients with TNBC with high expression of SCAMP3 showed decreased RFS and DMFS. Our findings indicate that SCAMP3 could contribute to TNBC development through the regulation of multiple pathways and has the potential to be a target for breast cancer therapy.