A critical mechanism that has been proposed for transcription regulation by estrogen receptor α (ER) is the tethering of ER to DNA via other transcription factors, such as AP-1. However, genome-wide assessment of the overlap in chromatin binding repertoires of these two transcription factors has not been reported. Here, we show that the AP-1 transcription factor c-Jun interacts with ER and that c-Jun chromatin binding shows extensive overlap with ER binding at the global level. Further, we show that c-Jun overexpression reprograms ER chromatin binding and modulates ER-mediated gene regulation. Our data are consistent with a mechanism where estrogen/ER-dependent crosstalk with AP-1 at the transcriptional level is mediated through the tethering of ER to DNA bound AP-1. Additionally, in our system c-Jun overexpression causes reduced sensitivity to tamoxifen in ER+ breast cancer cells. Integrated cistrome, transcriptome, and clinical data reveal TGFBI as a candidate gene which may confer tamoxifen resistance by ER and AP-1 crosstalk. Further, we show that TGFBI expression is elevated in breast cancer compared to normal breast. Together, our data provide a novel genome-wide footprint of ER and AP-1 crosstalk and suggest AP-1 and TGFBI signaling as potential therapeutic targets in AP-1-overexpressing ER-positive breast tumors.

中文翻译：

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c-Jun/AP-1 过表达重编程与 ERα 阳性乳腺癌中他莫昔芬反应相关的 ERα 信号传导。

已经提出的雌激素受体α (ER) 转录调控的一个关键机制是通过其他转录因子（例如 AP-1）将 ER 束缚在 DNA 上。然而，尚未报道对这两种转录因子染色质结合库重叠的全基因组评估。在这里，我们显示 AP-1 转录因子 c-Jun 与 ER 相互作用，并且 c-Jun 染色质结合在全球水平上与 ER 结合显示出广泛的重叠。此外，我们显示 c-Jun 过表达重新编程 ER 染色质结合并调节 ER 介导的基因调控。我们的数据与一种机制一致，其中雌激素/ER 依赖性与 AP-1 在转录水平上的串扰是通过 ER 与 DNA 结合的 AP-1 的束缚来介导的。此外，在我们的系统中，c-Jun 过表达导致 ER+ 乳腺癌细胞对他莫昔芬的敏感性降低。综合cistrome、转录组和临床数据显示TGFBI是一个候选基因，它可能通过ER和AP-1串扰赋予他莫昔芬抗性。此外，我们表明与正常乳房相比，乳腺癌中的 TGFBI 表达升高。总之，我们的数据提供了一种新的 ER 和 AP-1 串扰的全基因组足迹，并表明 AP-1 和 TGFBI 信号可以作为 AP-1 过表达 ER 阳性乳腺肿瘤的潜在治疗靶点。