Differential effects of HTLV-1 Tax oncoprotein on the different estrogen-induced-ER α-mediated transcriptional activities

Abstract

The activated estrogen (E2) receptor α (ERα) is a potent transcription factor that is involved in the activation of various genes by 2 different pathways; a classical and non-classical. In classical pathway, ERα binds directly to E2-responsive elements (EREs) located in the appropriate genes promoters and stimulates their transcription. However, in non-classical pathway, the ERα can indirectly bind with promoters and enhance their activity. For instance, ERα activates BRCA1 expression by interacting with jun/fos complex bound to the AP-1 site in BRCA1 promoter. Interference with the expression and/or functions of BRCA1, leads to high risk of breast or/and ovarian cancer. HTLV-1Tax was found to strongly inhibit BRCA1 expression by preventing the binding of E2-ERα complex to BRCA1 promoter. Here we examined Tax effect on ERα induced activation of genes by the classical pathway by testing its influence on E2-induced expression of ERE promoter-driven luciferase reporter (ERE-Luc). Our findings showed that E2 profoundly stimulated this reporter expression and that HTLV-1Tax significantly induced this stimulation. This result is highly interesting because in our previous study Tax was found to strongly block the E2-ERα-mediated activation of BRCA1 expression. ERα was found to produce a big complex by recruiting various cofactors in the nucleus before binding to the ERE region. We also found that only part of the reqruited cofactors are required for the transcriptional activity of ERα complex. Chip assay revealed that the binding of Tax to the ERα complex, did not interfere with its link to ERE region.

Mechanisms of resistance in estrogen receptor positive breast cancer: overcoming resistance to tamoxifen/aromatase inhibitors

“…Known mechanisms of resistance to hormone therapies are complex and include epigenetic regulation of ESR1 expression [5,6], ESR1 mutations [7–12], alternative splicing events [3], ESR1 truncation and fusion events [13], post-translational modifications [14,15], alterations in the hormone binding domain [7,16], alter-native recruitment sites within the genome [17], differential recruitment of coregulators [18], feedback loops by ER target genes on expression/activity of ER [19 ● ], downstream actions of ER target genes on growth factor pathways and other signaling networks [20,21 ●● ], influences of the tumor microenvironment [22], and many others (Figure 1). The details of these mechanisms are beyond the scope of this review but have been thoroughly described by others [23,24].…”

Effect of TPA and HTLV-1 Tax on BRCA1 and ERE controlled genes expression

“…HTLV-1 Tax onc-protein was found in our previous study to stimulate the transcriptional activity of ERa through the classical pathway (inducing the expression of genes controlled by ERE sequences) while it strongly inhibited BRCA1 expression through the non-classical pathway of ERa. 37,59 TPA which is known as a potent PKC activator and involved in the promotion of various kinds of tumors 51,52 was previously found to induce the expression of HTLV-1. 46,48,49,53 In the present study we examined the effect of TPA treatment on the expression of BRCA1 and genes controlled by ERE sequences in MCF-7 cells with or without Tax expression.…”

“…66 It was concluded that the inhibitory effects of TPA on the growth stimulation of MCF-7 cells by E2 was not due to a general inhibition of the expression of E2 responsive genes but probably due to a stimulation of TGF-b 1, acting as an autocrine inhibitory growth factor. 66 Based on our previous studies which showed that Tax strongly inhibited the E2-ERa induced activation of BRCA1 expression while stimulating E2-ERa induced activation of ERE dependent genes, 37,59 it was important to find out whether Tax has any effect on TPA activities on BRCA1 and ERE responsive genes. The results of this study showed that Tax has only minor inhibitory effect on TPA stimulation of BRCA1 (Fig.…”

“…In our previous study it was found that HTLV-1 Tax strongly prevented the E2-ERa induced expression of BRCA1, while it stimulated the E2-ERa induced expression of genes that contain estrogen responsive elements (EREs) in their promotors. 59 Based on these results we hypothesized that the expression of HTLV-1 Tax in breast epithelial cells may increase the risk for breast cancer development.…”

Isobavachalcone sensitizes cells to E2‐induced paclitaxel resistance by down‐regulating CD44 expression in ER+ breast cancer cells

“…ERα can act as a nuclear receptor and regulate target gene transcription via the “classical” model or the “nonclassical” model . In addition to its role in the “classical” model of gene regulation through oestrogen response elements (EREs) in promoter regions, ERα can form protein complexes with other transcription factors, such as Sp1, Ap1 and NF‐κB, to regulate gene transcription involved in the “nonclassical” model . These observations suggest that ERα can regulate a large variety of genes that are associated with the development of chemotherapy resistance in ER+ breast cancer cells.…”