Protease Nexin I is a feedback regulator of EGF/PKC/MAPK/EGR1 signaling in breast cancer cells metastasis and stemness.

Abstract

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.

• Authors: Tingting Tang, Qinhua Zhu, Xinping Li, Gaole Zhu, Siwei Deng, Yingshan Wang, Lingyu Ni, Xinyuan Chen, Yanfeng Zhang, Tiansong Xia, Ke Zen, Yi Pan, Liang Jin
• Journal: Cell death & disease (Cell Death Dis) Vol. 10 Issue 9 Pg. 649 (09 09 2019) ISSN: 2041-4889 [Electronic] England
• PMID: 31501409 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• EGR1 protein, human
• Early Growth Response Protein 1
• RNA, Small Interfering
• Serpin E2
• Epidermal Growth Factor
• Protein Kinase C

Topics

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