Impaired redox regulation of estrogen metabolizing proteins is important determinant of human breast cancers

Abstract

Estrogen evidently involves critically in the pathogenesis of gynaecological-cancers. Reports reveal that interference in estrogen-signalling can influence cell-cycle associated regulatory-processes in female reproductive-organs. The major determinants that influence E2-signallings are estrogen-receptor (ER), estrogen-sulfotransferase (SULT1E1), sulfatase (STS), and a formylglycine-generating-enzyme (FGE) which regulates STS activity. The purpose of this mini review was to critically analyze the correlation between oxidative-threats and redox-regulation in the process of estrogen signalling. It is extensively investigated and reported that oxidative-stress is linked to cancer. But no definite mechanism has been explored till date. The adverse effects of oxidative-threat/free-radicals (like genotoxic-effects, gene-regulation, and mitochondrial impairment) have been linked to several diseases like diabetes/cardiovascular-syndrome/stroke and cancer. However, a significant correlation between oxidative-stress and gynaecological-cancers are repeatedly reported without pointing a definite mechanism. For the first time in our study we have investigated the relationship between oxidative stress and the regulation of estrogen via estrogen metabolizing proteins. Reports reveal that ER, SULT1E1, STS and FGE are target-molecules of oxidative-stress and may function differently in oxidizing and reducing environment. In addition, estrogen itself can induce oxidative-stress. This fact necessitates identifying the critical connecting events between oxidative-stress and regulation of estrogen-associated-molecules (ER, SULT1E1, STS, and FGE) that favors tumorigenesis/carcinogenesis. The current review focus is on unique redox-regulation of estrogen and its regulatory-molecules via oxidative-stress. This mechanistic-layout may identify new therapeutic-targets and open further scopes to treat gynecological-cancers more effectively.

Keywords: ERα positive; Estrogen; Estrogen sulfatase; Formylglycine generating enzyme; Gynecological cancers; hSULT1E1.

Fig. 1

E2-ER complexes binds to EREs and also to transcription factor complexes, e.g. AP-1, STATs, ATF2 (activation transcription factor 2)/c-Jun, Sp1, and NFκβ that are already bound to their specific DNA binding sites Membrane E2-ER complexes activate protein-kinase cascades, leading to phosphorylation (P) of target transcription factors, e.g. AP-1, STATs, Elk-1, SRF (serum response factor), CREB and NFκB. The phosphorylation results in their transcriptional activation or modulation of the transcriptional activities of ER-AP-1, ER-STAT, ER-Sp1, and ER-NFκB complexes. Protein-kinase phosphorylates ERs resulting in ligand independent transcriptional activity

Fig. 2

ERα+ cells expresses FGF9 TBX3, TBX3 further expresses FGF and Wnt, Wnts bind to LRP receptors which transduces a signal to β-catenin, β-catenin binds to TCF to transcript Wnt genes

Fig. 3

E2 controls the ER− stem or non stem cell in a paracrine manner, the self renewal of Erα− stem cells and its differentiation into Erα+ cells depends on amphiregulin secreted by Erα+ cells. Presence of ER+ stem cell inhibits proliferation of Erα− stem cells

Fig. 4

Estrogen induces production of ROS when semiquinones are converted to o-quinones

Fig. 5

High oxidative stress upregulates Sulfatase and downregulates estrogen sulfotransferase resulting in high E2 and low E2s and vice versa