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Single-cell transcriptome analysis reveals estrogen signaling augments the mitochondrial folate pathway to coordinately fuel purine and polyamine synthesis in breast cancer cells

By Detu Zhu, Xianglan Zhaozu, Guimei Cui, Shiehong Chang, Yi Xiang See, Michelle Gek Liang Lim, Dajiang Guo, Xin Chen, Paul Robson, Yumei Luo, Edwin Cheung

Posted 16 Jan 2018
bioRxiv DOI: 10.1101/246363 (published DOI: 10.1016/j.celrep.2018.10.093)

Estrogen regulates diverse physiological effects and drives breast tumor progression by directly activating estrogen receptor α (ERα). However, due to the stochastic nature of gene transcription and the resulting heterogeneous cellular response, it is important to investigate estrogen-stimulated gene expression profiles at the single-cell level in order to fully understand how ERα regulates transcription in breast cancer cells. In this study, we performed single-cell transcriptome analysis on ERα-positive breast cancer cell lines following 17β-estradiol stimulation. Overall, we observed robust gene expression diversity between individual cells. Moreover, we found over two thirds of the genes in breast cancer cells displayed a bimodal expression pattern, which caused averaging artifacts and masked the identification of potential estrogen-regulated genes. We overcame this issue by reconstructing a dynamic estrogen-responsive transcriptional network from discrete time points into a pseudotemporal continuum. Pathway analysis of the differentially expressed genes derived from the pseudotemporal analysis showed an estrogen-stimulated metabolic switch that favored biosynthesis and cell proliferation but reduced estrogen degradation. In addition, we identified folate-mediated one-carbon metabolism as a novel estrogen-regulated pathway in breast cancer cells. Notably, estrogen stimulation reprogramed this pathway through the mitochondrial folate pathway to coordinately fuel polyamine and de novo purine synthesis. Finally, we showed AZIN1 and PPAT, key regulators in the above pathways, are direct ERα target genes and essential for breast cancer cell survival and growth. In summary, our single-cell study illustrated a dynamic transcriptional heterogeneity in ERα-positive breast cancer cells in response to estrogen stimulation and uncovered a novel mechanism of an estrogen-mediated metabolic switch.

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