Cancer Centre, University of Macau, Avenida da Universidade, Taipa, Macau, China; Centre of Precision Medicine Research and Training, Faculty of Health Sciences, University of Macau, Avenida da Universidade, Taipa, Macau, China.
Genome Institute of Singapore, A(∗)STAR (Agency for Science, Technology and Research), Singapore, Singapore.
Cell Rep. 2018 Nov 20;25(8):2285-2298.e4. doi: 10.1016/j.celrep.2018.10.093.
Estrogen drives breast cancer (BCa) progression by directly activating estrogen receptor α (ERα). However, because of the stochastic nature of gene transcription, it is important to study the estrogen signaling pathway at the single-cell level to fully understand how ERα regulates transcription. Here, we performed single-cell transcriptome analysis on ERα-positive BCa cells following 17β-estradiol stimulation and reconstructed the dynamic estrogen-responsive transcriptional network from discrete time points into a pseudotemporal continuum. Notably, differentially expressed genes show an estrogen-stimulated metabolic switch that favors biosynthesis but reduces estrogen degradation. Moreover, folate-mediated one-carbon metabolism is reprogrammed through the mitochondrial folate pathway and polyamine and purine synthesis are upregulated coordinately. Finally, we show AZIN1 and PPAT are direct ERα targets that are essential for BCa cell survival and growth. In summary, our study highlights the dynamic transcriptional heterogeneity in ERα-positive BCa cells upon estrogen stimulation and uncovers a mechanism of estrogen-mediated metabolic switch.
雌激素通过直接激活雌激素受体 α（ERα）驱动乳腺癌（BCa）的进展。然而，由于基因转录的随机性，有必要在单细胞水平上研究雌激素信号通路，以充分了解 ERα 如何调节转录。在这里，我们对 17β-雌二醇刺激后的 ERα 阳性 BCa 细胞进行了单细胞转录组分析，并将离散时间点的动态雌激素反应转录网络重构为伪时间连续体。值得注意的是，差异表达基因显示出雌激素刺激的代谢开关，有利于生物合成但减少雌激素降解。此外，叶酸介导的一碳代谢通过线粒体叶酸途径重新编程，多胺和嘌呤合成协同上调。最后，我们表明 AZIN1 和 PPAT 是 ERα 的直接靶标，对于 BCa 细胞的存活和生长是必需的。总之，我们的研究强调了雌激素刺激下 ERα 阳性 BCa 细胞中的动态转录异质性，并揭示了雌激素介导的代谢开关的机制。
