Eeckhoute Jérôme, Carroll Jason S, Geistlinger Timothy R, Torres-Arzayus Maria I, Brown Myles
Division of Molecular and Cellular Oncology, Department of Medical Oncology, Dana-Farber Cancer Institute and Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts 02115, USA.
Genes Dev. 2006 Sep 15;20(18):2513-26. doi: 10.1101/gad.1446006.
Estrogen stimulates the proliferation of the most common type of human breast cancer that expresses estrogen receptor alpha (ERalpha) through the activation of the cyclin D1 (CCND1) oncogene. However, our knowledge of ERalpha transcriptional mechanisms remains limited. Hence, it is still elusive why ERalpha ectopically expressed in ER-negative breast cancer cells (BCC) is functional on ectopic reporter constructs but lacks activity on many endogenous target genes, including CCND1. Here, we show that estradiol (E2) stimulation of CCND1 expression in BCC depends on a novel cell-type-specific enhancer downstream from the CCND1 coding region, which is the primary ERalpha recruitment site in estrogen-responsive cells. The pioneer factor FoxA1 is specifically required for the active chromatin state of this enhancer and as such is crucial for both CCND1 expression and subsequent cell cycle progression. Interestingly, even in BCC, CCND1 levels and proliferation are tightly controlled by E2 through the establishment of a negative feedforward loop involving the induction of NFIC, a putative tumor suppressor capable of directly repressing CCND1 transcription. Taken together, our results reveal an estrogen-regulated combinatorial network including cell-specific cis- and trans-regulators of CCND1 expression where ERalpha collaborates with other transcription factors associated with the ER-positive breast cancer phenotype, including FoxA1 and NFIC.
雌激素通过激活细胞周期蛋白D1（CCND1）癌基因，刺激表达雌激素受体α（ERα）的最常见类型的人类乳腺癌细胞增殖。然而，我们对ERα转录机制的了解仍然有限。因此，目前仍不清楚为什么在雌激素受体阴性乳腺癌细胞（BCC）中异位表达的ERα在异位报告基因构建体上具有功能，但对包括CCND1在内的许多内源性靶基因却缺乏活性。在这里，我们表明，BCC中雌二醇（E2）对CCND1表达的刺激依赖于CCND1编码区下游一个新的细胞类型特异性增强子，该增强子是雌激素反应性细胞中主要的ERα募集位点。先驱因子FoxA1是该增强子活性染色质状态所特需的，因此对CCND1表达和随后的细胞周期进程都至关重要。有趣的是，即使在BCC中，E2也通过建立一个负反馈前馈环来严格控制CCND1水平和细胞增殖，该负反馈前馈环涉及诱导NFIC，NFIC是一种可能的肿瘤抑制因子，能够直接抑制CCND1转录。综上所述，我们的结果揭示了一个雌激素调节的组合网络，包括CCND1表达的细胞特异性顺式和反式调节因子，其中ERα与其他与雌激素受体阳性乳腺癌表型相关的转录因子（包括FoxA1和NFIC）协同作用。
