J Cancer Prev.  2021 Mar;26(1):54-63. 10.15430/JCP.2021.26.1.54.

Heregulin-β1 Activates NF-E2-related Factor 2 and Induces Manganese Superoxide Dismutase Expression in Human Breast Cancer Cells via Protein Kinase B and Extracellular Signal-regulated Protein Kinase Signaling Pathways

Affiliations
  • 1Tumor Microenvironment Global Core Research Center, College of Pharmacy, Seoul National University, Seoul, Korea
  • 2Department of Molecular Medicine and Biopharmaceutical Sciences, Graduate School of Convergence Science and Technology, Seoul National University, Seoul, Korea
  • 3College of Pharmacy and Institute of Pharmaceutical Sciences, CHA University, Seongnam, Korea
  • 4Department of Chemistry, College of Convergence and Integrated Science, Kyonggi University, Suwon, Korea
  • 5Department of Food Science and Biotechnology, College of Knowledge-Based Services Engineering, Sungshin Women’s University, Seoul, Korea
  • 6Medical University of South Carolina, Charleston, SC, USA
  • 7Department of Pathology, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul, Korea

Abstract

Heregulin-β1, a ligand of ErbB-2 and ErbB-3/4 receptors, has been reported to potentiate oncogenicity and metastatic potential of breast cancer cells. In the present work, treatment of human mammary cancer (MCF-7) cells with heregulin-β1 resulted in enhanced cell migration and expression of manganese superoxide dismutase (MnSOD) and its mRNA transcript. Silencing of MnSOD abrogated clonogenicity and migrative ability of MCF-7 cells. Heregulin-β1 treatment also increased nuclear translocation, antioxidant response element binding and transcriptional activity of NF-E2-related factor 2 (Nrf2). A dominant-negative mutant of Nrf2 abrogated heregulin-β1-induced MnSOD expression. Treatment with heregulin-β1 caused activation of protein kinase B (Akt) and extracellular signal-regulated protein kinase (ERK). The pharmacological inhibitors of phosphatidylinositol 3-kinase and mitogen-activated protein kinase kinase 1/2, which are upstream of Akt and ERK, respectively, attenuated heregulin-β1-induced MnSOD expression and nuclear localization of Nrf2. In conclusion, heregulin-1 induces upregulation of MnSOD and activation of Nrf2 via the Akt and ERK signaling in MCF-7 cells, which may confer metastatic potential and invasiveness of these cells.

Keyword

Breast cancer; Heregulin-β1; Manganese superoxide dismutase; NF-E2-related factor 2
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