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Breast cancer is the most prevalent cancer in women worldwide, which remains incurable once metastatic. Breast cancer stem cells (BCSCs) are a small subset of breast cancer cells, which are the radical cause of drug resistance, tumor relapse, and metastasis in breast cancer. The extracellular serine protease inhibitor serpinE2, also named protease nexin-1 (PN-1), contributes to enhanced metastasis of cancer cells mainly by remodeling the tumor matrix. In this study, we found that PN-1 was up-regulated in breast cancer, which promoted cell invasion, migration and stemness. Furthermore, by using specific inhibitors, we discovered that epidermal growth factor (EGF) up-regulated PN-1 in breast cancer cells through cascade activation of epidermal growth factor receptor (EGFR) to the activation of protein kinase Cδ (PKCδ), mitogen-activated protein kinase (MEK) and extracellular signal-related kinase (ERK), which finally led to the up-regulation of early growth response protein 1 (EGR1). Moreover, EGF signaling was further activated as a feedback of PN-1 up-regulation through PN-1 blocking HtrA1. Taken together, our findings revealed a novel signaling axis that up-regulated PN-1 expression in breast cancer cells, and the new mechanism of PN-1-promoted breast cancer metastasis, which may provide new insights into identifying novel therapeutic targets for breast cancer.

Original publication

DOI

10.1038/s41419-019-1882-9

Type

Journal article

Journal

Cell death dis

Publication Date

09/09/2019

Volume

10

Keywords

Animals, Blotting, Western, Breast Neoplasms, Cell Line, Tumor, Cell Movement, Cells, Cultured, Chromatin Immunoprecipitation, Early Growth Response Protein 1, Enzyme-Linked Immunosorbent Assay, Epidermal Growth Factor, Female, Flow Cytometry, Fluorescent Antibody Technique, Gene Expression Regulation, Neoplastic, Humans, MCF-7 Cells, Mice, Mice, Inbred BALB C, Mice, Nude, Neoplasm Recurrence, Local, Neoplastic Stem Cells, Protein Kinase C, RNA, Small Interfering, Serpin E2, Signal Transduction