Research Papers:

This article has been corrected. Correction in: Oncotarget. 2019; 10:1266.

4-Hydroxyestradiol induces mammary epithelial cell transformation through Nrf2-mediated heme oxygenase-1 overexpression

Sin-Aye Park, Mee-Hyun Lee, Hye-Kyung Na and Young-Joon Surh _

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Oncotarget. 2017; 8:164-178. https://doi.org/10.18632/oncotarget.10516

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Sin-Aye Park1, Mee-Hyun Lee1, Hye-Kyung Na4, Young-Joon Surh1,2,3

1Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul 08826, South Korea

2Department of Molecular Medicine and Biopharmaceutical Sciences, Graduate School of Convergence Science and Technology, Seoul National University, Seoul 08826, South Korea

3Cancer Research Institute, Seoul National University, Seoul 110-799, South Korea

4Department of Food and Nutrition, College of Human Ecology, Sungshin Women’s University, Seoul 136-742, South Korea

Correspondence to:

Young-Joon Surh, email: [email protected] snu.ac.kr

Keywords: 4-hydroxyestradiol, heme oxygenase-1, catechol estrogen, Nrf2, breast cancer

Received: January 25, 2016     Accepted: May 12, 2016     Published: July 09, 2016


Estrogen (17β-estradiol, E2) undergoes oxidative metabolism by CYP1B1 to form 4-hydroxyestradiol (4-OHE2), a putative carcinogenic metabolite of estrogen. Our previous study showed that 4-OHE2-induced production of reactive oxygen species contributed to neoplastic transformation of human breast epithelial (MCF-10A) cells. In this study, 4-OHE2, but not E2, increased the expression of heme oxygenase-1 (HO-1), a sensor and regulator of oxidative stress, in MCF-10A cells. Silencing the HO-1 gene in MCF-10A cells suppressed 4-OHE2-induced cell proliferation and transformation. In addition, subcutaneous administration of 4-OHE2 markedly enhanced the growth of the MDA-MB-231 human breast cancer xenografts, which was retarded by zinc protoporphyrin, a pharmacological inhibitor of HO-1. 4-OHE2-induced HO-1 expression was mediated by NF-E2-related factor 2 (Nrf2). We speculate that an electrophilic quinone formed as a consequence of oxidation of 4-OHE2 binds directly to Kelch-like ECH-associated protein 1 (Keap1), an inhibitory protein that sequesters Nrf2 in the cytoplasm. This will diminish association between Nrf2 and Keap1. 4-OHE2 failed to interrupt the interaction between Keap1 and Nrf2 and to induce HO-1 expression in Keap1-C273S or C288S mutant cells. Lano-LC-ESI-MS/MS analysis in MCF-10A-Keap1-WT cells which were treated with 4-OHE2 revealed that the peptide fragment containing Cys288 gained a molecular mass of 287.15 Da, equivalent to the addition of a single molecule of 4-OHE2-derived ortho-quinones.

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