HTLV-1 Tax Oncoprotein Inhibits the Estrogen-Induced-ER α-Mediated BRCA1 Expression by Interaction with CBP/p300 Cofactors

Abstract

BRCA1 is a multifunctional tumor suppressor, whose expression is activated by the estrogen (E2)-liganded ERα receptor and regulated by certain recruited transcriptional co-activators. Interference with BRCA1 expression and/or functions leads to high risk of breast or/and ovarian cancer. Another multifunctional protein, HTLV-1Tax oncoprotein, is widely regarded as crucial for developing adult T-cell leukemia and other clinical disorders. Tax profile reveals that it can antagonize BRCA1 expression and/or functionality. Therefore, we hypothesize that Tax expression in breast cells can sensitize them to malignant transformation by environmental carcinogens. Here we examined Tax effect on BRCA1 expression by testing its influence on E2-induced expression of BRCA1 promoter-driven luciferase reporter (BRCA1-Luc). We found that E2 strongly stimulated this reporter expression by liganding to ERα, which consequently associated with BRCA1 promoter, while ERα concomitantly recruited CBP/p300 to this complex for co-operative enhancement of BRCA1 expression. Introducing Tax into these cells strongly blocked this E2-ERα-mediated activation of BRCA1 expression. We noted, also, that Tax exerted this inhibition by binding to CBP/p300 without releasing them from their complex with ERα. Chip assay revealed that the binding of Tax to the CBP/p300-ERα complex, prevented its link to AP1 site. Interestingly, we noted that elevating the intracellular pool of CBP or p300 to excessive levels dramatically reduced the Tax-mediated inhibition of BRCA1 expression. Exploring the mechanism of this reduction revealed that the excessive co-factors were sufficient to bind separately the free Tax molecules, thus lowering their amount in the CBP/p300-ERα complex and relieving, thereby, the inhibition of BRCA1 expression.

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

“…[26][27][28][29] Therefore, we speculate that if expressed in breast cells, Tax would be able to block the expression and most of the activities of BRCA1. This speculation is supported by our previous study, 62 which show, for the first time, that Tax inhibits basal and E2-stimulated BRCA1 expression in breast cells by preventing the binding of ER-a transcriptional complex to BRCA1 promoter. It thus appears likely that in breast cells Tax can potentially create a BRCA1-deficient microenvironment that usually leads to breast cancer development.…”

“…3.1 Effect of HTLV-1 Tax varients on the E2-induced BRCA1-Luc and ERE-Luc expression. In extention to our previous findings 62 which proved the potential of HTLV-1 Tax protein to significantly prevent the E2 induced BRCA1 expression, we examined in this study the effect of HTLV-1 Tax on the E2 induced expression of genes controlled by promoters containing the ERE sequences in comparison with its effect on BRCA1 expression. This was done by examining the effect of Taxexpressing vector on the expression of ERE-Luc or BRCA1-Luc in MCF-7 cells.…”

Clinical Features of Breast Cancer Patients with Human T-Cell Lymphotropic Virus Type-1 Infection

“…Overall, Satake et al (2012) reported that the number of HTLV-1 carriers has decreased 10% over the past 2 decades (1980s to 2000s), so the age distribution of carriers has trended Tax1 has been reported to promote cancer cell proliferation via the Ras-Raf-MEK-ERK signaling pathway (Song et al, 2009). In addition, Tax1 sensitizes breast cancer cells to malignant transformation induced by environmental carcinogens through the inhibition of estrogen-induced ERα-mediated BRCA1 expression (Shukrun et al, 2014). Thus, we hypothesized that HTLV-1 infection is associated with breast cancer progression.…”

Epigenetic Pathways of Oncogenic Viruses: Therapeutic Promises

“…Tax‐mediated BRCA1 inhibition provides information regarding the relationship between HTLV‐1 infection and the development of breast cancer because of the importance of BRCA1 as a predisposing factor in this disease. HTLV‐1 infection and penetration into breast cells are speculated to play a positive role in mammary tumorigenesis .…”