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.jpg): Failed to open stream: No such file or directory in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 117 Oncotarget
2017 ; 8
(1
): 164-178
Nephropedia Template TP
Oncotarget
2017[Jan]; 8
(1
): 164-178
PMID27438141
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Estrogen (17?-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.