University of Oulu

Urpilainen, E., Kangaskokko, J., Puistola, U., & Karihtala, P. (2019). Metformin diminishes the unfavourable impact of Nrf2 in breast cancer patients with type 2 diabetes. Tumor Biology. https://doi.org/10.1177/1010428318815413

Metformin diminishes the unfavourable impact of Nrf2 in breast cancer patients with type 2 diabetes

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Author: Urpilainen, Elina1; Kangaskokko, Jenni2; Puistola, Ulla1;
Organizations: 1Department of Obstetrics and Gynaecology, PEDEGO Research Unit and Medical Research Center Oulu, University of Oulu and Oulu University Hospital, Oulu, Finland
2Department of Pathology and Medical Research Center Oulu, University of Oulu and Oulu University Hospital, Oulu, Finland
3Department of Oncology and Radiotherapy and Medical Research Center Oulu, University of Oulu and Oulu University Hospital, Oulu, Finland
Format: article
Version: published version
Access: open
Online Access: PDF Full Text (PDF, 2.2 MB)
Persistent link: http://urn.fi/urn:nbn:fi-fe202003057345
Language: English
Published: SAGE Publications, 2019
Publish Date: 2020-03-05
Description:

Abstract

Nuclear factor (erythroid-derived 2)-like 2 (Nrf2) is a major regulator of the oxidative stress response and it is negatively regulated by Kelch-like ECH-associated protein 1 (Keap1). The Keap1–Nrf2 axis has a fundamental role in carcinogenesis. In previous studies, the widely used diabetes drug metformin has appeared to have a critical role in the regulation of Nrf2 function. In this study, we assessed the expression of Nrf2 and Keap1 immunohistochemically in 157 patients with type 2 diabetes who underwent breast cancer surgery with curative intent. In total, 78 (49.7%) of these patients were taking metformin alone or combined with other oral anti-diabetic medication at the time of breast cancer diagnosis. We found that high-level cytoplasmic Nrf2 expression predicted dismal overall survival and breast cancer–specific survival, but only in the patients who were not taking metformin at the time of diagnosis. Similarly, low-level nuclear Keap1 expression had an adverse prognostic value in terms of overall survival and breast cancer–specific survival in patients without metformin. On the other hand, high-level nuclear Keap1 expression was associated with prolonged overall survival and breast cancer–specific survival. The results may be explained in terms of non-functioning or displaced Keap1, although more mechanistic pre-clinical and prospective clinical studies are warranted.

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Series: Tumor biology
ISSN: 1010-4283
ISSN-E: 1423-0380
ISSN-L: 1010-4283
Volume: 41
Issue: 1
Pages: 1 - 10
DOI: 10.1177/1010428318815413
OADOI: https://oadoi.org/10.1177/1010428318815413
Type of Publication: A1 Journal article – refereed
Field of Science: 3122 Cancers
Subjects:
Funding: This study was funded by grants from the Jane and Aatos Erkko Foundation, the Cancer Society of Finland, the Cancer Society of Northern Finland and Finnish Government Research Funds granted to the University Hospital of Oulu.
Copyright information: © The Author(s) 2019. This article is distributed under the terms of the Creative CommonsAttribution-NonCommercial 4.0 License (http://www.creativecommons.org/licenses/by-nc/4.0/) which permits non-commercial use, reproduction and distribution of the work without further permission provided the original work is attributed as specified on the SAGE and Open Access pages (https://us.sagepub.com/en-us/nam/open-access-at-sage.
  https://creativecommons.org/licenses/by-nc/4.0/