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Journal of Cancer Prevention

Original Article

J Cancer Prev 2021; 26(1): 54-63

Published online March 30, 2021

© Korean Society of Cancer Prevention

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

Ji-Young Park1 , Soma Saeidi1,2 , Eun-Hee Kim3 , Do-Hee Kim4 , Hye-Kyung Na5 , Joo-Seob Keum6,7 , Young-Joon Surh1,2

1Tumor Microenvironment Global Core Research Center, College of Pharmacy, Seoul National University, Seoul, 2Department of Molecular Medicine and Biopharmaceutical Sciences, Graduate School of Convergence Science and Technology, Seoul National University, Seoul, 3College of Pharmacy and Institute of Pharmaceutical Sciences, CHA University, Seongnam, 4Department of Chemistry, College of Convergence and Integrated Science, Kyonggi University, Suwon, 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

Correspondence to :
Young-Joon Surh, E-mail:,

Received: January 5, 2021; Revised: February 6, 2021; Accepted: February 15, 2021

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License, which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original work is properly cited.


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 Mn-SOD 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 Mn-SOD 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.

Keywords: Breast cancer, Heregulin-β1, Manganese superoxide dismutase, NF-E2-related factor 2


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