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.
Highlights
Breast cancer is a complex malignancy with several phenotypic characteristics that might be determined by several gene products and certain additional intrinsic or/and external factors [1]
The effect of human T-cell leukemia virus type 1 (HTLV-1) Tax oncoprotein on the expression of BRCA1 in E2-treated breast cells and its molecular mechanism were investigated in this study
Consistent with earlier reports [14,15,16], we demonstrated that E2 profoundly induced BRCA1 expression in various breast cell lines by liganding its E2 receptor alpha (ERa) receptor
Summary
Breast cancer is a complex malignancy with several phenotypic characteristics that might be determined by several gene products and certain additional intrinsic or/and external factors [1]. Malfunction of the first discovered breast cancer sensitivity gene product, BRCA1, has been recognized as the most frequent risk factor for this mammary tumorigenesis. Between 5 to 10% of breast cancer cases arise at early stages of women’s life in hereditary manner due to inheriting germ-line genetic factors. Half of these early breast cancers proved to emerge from germ-line mutations within the BRCA1 gene, which hamper the expression or functions of its protein [2]. Mutations within the BRCA1 gene are rare (2–3%) in such sporadic cases [2], the level of BRCA1 protein in cancerous breast cells of 30–40% of the sporadic breast cancers is markedly reduced by various non-mutational down-regulating mechanisms [4], indicating that BRCA1 malfunction is a major risk factor which is associated with sporadic breast cancers as well
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