PBX1 genomic pioneer function drives ERα signaling underlying progression in breast cancer.
PBX1 genomic pioneer function drives ERα signaling underlying progression in breast cancer.
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DOI：
10.1371/journal.pgen.1002368
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发表时间：
2011-11
期刊：
影响因子：
4.5
通讯作者：
Lupien M
中科院分区：
文献类型：
--
作者：
Magnani L;Ballantyne EB;Zhang X;Lupien M
转录程序的改变是疾病的一个标志，但这些程序是如何建立的仍然没有明确的定义。Pbx1是一种同源结构域蛋白，与不同类型癌症的发生有关。雌激素受体α(ER-α)在三分之二的乳腺癌的发生发展中起核心作用。在这里，我们证明了PBX1作为一个先锋因子，在ERα介导的转录反应驱动乳腺癌侵袭性肿瘤中是必不可少的。事实上，在原发性乳腺肿瘤中，PBX1的表达与ERα相关，并且在雌激素刺激下，缺失PBX1的乳腺癌细胞不再增殖。通过CHIP-SEQ和FIRE-SEQ分析Pbx1在乳腺癌细胞基因组中的募集和染色质的可及性，揭示了Pbx1被加载，并通过其读取特定表观遗传信号的能力促进了特定基因组位置的染色质开放。因此，Pbx1将ERα招聘引导到特定的站点子集。表达谱研究表明，Pbx1控制着超过70%的雌激素反应。更重要的是，依赖于Pbx1的转录程序与乳腺癌患者的不良预后有关。相应地，在ERα阳性的乳腺癌患者中，仅PBX1的表达就可以先验地区分预后。这些特征与以前表征的ERα相关的先锋因子FoxA1明显不同。事实上，Pbx1是迄今为止发现的唯一能区分ERα阳性乳腺癌患者转移等预后的先锋因子。综上所述，我们的结果表明，PBX1是定义侵袭性ERα阳性乳腺肿瘤的新的先驱因子，因为它引导ERα基因组活性到独特的基因组区域，促进有利于乳腺癌进展的转录程序。大约三分之二的乳腺癌生长依赖雌激素受体α(ERα)。它在雌激素刺激后作为转录因子结合DNA的能力是促进促肿瘤转录反应的关键。重要的是，根据结果可以区分不同类型的ERα阳性乳腺肿瘤。然而，推动这些差异的潜在机制尚不清楚。在这里，我们证明了Pbx1作为先驱因子识别特定的表观遗传修饰来重塑染色质并引导ERα基因组活性。这转化为一种特定的转录程序，与乳腺癌患者的不良结局相关。更重要的是，仅PBX1的表达就足以确定先天ERα阳性的乳腺癌患者有发生转移的风险。总体而言，这项研究定义了依赖于先锋因子PBX1的机制，该因子在ERα阳性乳腺癌的子集中驱动侵袭性反应。这些特征突出了Pbx1的独特性，并证明了其潜在的预后价值。
Altered transcriptional programs are a hallmark of diseases, yet how these are established is still ill-defined. PBX1 is a TALE homeodomain protein involved in the development of different types of cancers. The estrogen receptor alpha (ERα) is central to the development of two-thirds of all breast cancers. Here we demonstrate that PBX1 acts as a pioneer factor and is essential for the ERα-mediated transcriptional response driving aggressive tumors in breast cancer. Indeed, PBX1 expression correlates with ERα in primary breast tumors, and breast cancer cells depleted of PBX1 no longer proliferate following estrogen stimulation. Profiling PBX1 recruitment and chromatin accessibility across the genome of breast cancer cells through ChIP-seq and FAIRE-seq reveals that PBX1 is loaded and promotes chromatin openness at specific genomic locations through its capacity to read specific epigenetic signatures. Accordingly, PBX1 guides ERα recruitment to a specific subset of sites. Expression profiling studies demonstrate that PBX1 controls over 70% of the estrogen response. More importantly, the PBX1-dependent transcriptional program is associated with poor-outcome in breast cancer patients. Correspondingly, PBX1 expression alone can discriminate a priori the outcome in ERα-positive breast cancer patients. These features are markedly different from the previously characterized ERα-associated pioneer factor FoxA1. Indeed, PBX1 is the only pioneer factor identified to date that discriminates outcome such as metastasis in ERα-positive breast cancer patients. Together our results reveal that PBX1 is a novel pioneer factor defining aggressive ERα-positive breast tumors, as it guides ERα genomic activity to unique genomic regions promoting a transcriptional program favorable to breast cancer progression. Approximately two-thirds of breast cancers depend on the estrogen receptor alpha (ERα) for their growth. Its capacity to act as a transcription factor binding DNA following estrogen stimulation is central to promote a pro-tumorigenic transcriptional response. Importantly, different classes of ERα-positive breast tumors can be discriminated based on outcome. However, the underlying mechanisms driving these differences are unknown. Here we demonstrate that PBX1 acts as a pioneer factor recognizing a specific epigenetic modification to remodel chromatin and guide ERα genomic activity. This translates in a specific transcriptional program associated with poor-outcome in breast cancer patients. Even more, PBX1 expression alone is sufficient to identify a priori ERα-positive breast cancer patients at risk of developing metastasis. Overall, this study defines the mechanisms dependent on the pioneer factor PBX1 that drives an aggressive response in a subset of ERα-positive breast cancers. These features highlight the uniqueness of PBX1 and demonstrate its potential prognostic value.
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64.8
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