Abstract
An epithelial to mesenchymal transition (EMT) is an embryonic dedifferentiation program which is aberrantly activated in cancer cells to acquire cellular plasticity. This plasticity increases the ability of breast cancer cells to invade into surrounding tissue, to seed metastasis at distant sites and to resist to chemotherapy. In this study, we have observed a higher expression of interferon-related factors in basal-like and claudin-low subtypes of breast cancer in patients, known to be associated with EMT. Notably, Irf1 exerts essential functions during the EMT process, yet it is also required for the maintenance of an epithelial differentiation status of mammary gland epithelial cells: RNAi-mediated ablation of Irf1 in mammary epithelial cells results in the expression of mesenchymal factors and Smad transcriptional activity. Conversely, ablation of Irf1 during TGFβ-induced EMT prevents a mesenchymal transition and stabilizes the expression of E-cadherin. In the basal-like murine breast cancer cell line 4T1, RNAi-mediated ablation of Irf1 reduces colony formation and cell migration in vitro and shedding of circulating tumor cells and metastasis formation in vivo. This context-dependent dual role of Irf1 in the regulation of epithelial-mesenchymal plasticity provides important new insights into the functional contribution and therapeutic potential of interferon-regulated factors in breast cancer.
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Data availability
The RNA-sequencing and ChIP-sequencing data are deposited on GEO database under GSE141500 and GSE141501, respectively.
Supplementary information is available at www.nature.com/onc/.
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Acknowledgements
We thank Petra Schmidt for technical assistance with immunoblotting and quantitative RT-PCR, Helena Antoniadis for help with mouse work, Christian Beisel and the D-BSSE sequencing facility for RNA-sequencing, Pascal Lorenz and the DBM Mattenstrasse microscopy facility for microscopy and image quantification support. This work was supported by the Swiss National Science Foundation (310030B_163471), the SystemsX.ch RTD Cellplasticity, the Swiss Cancer League (KFS-3479-08-2014), the Krebsliga Beider Basel (03-2013) (all GC) and by a Marie-Heim Vögtlin grant from the Swiss National Science Foundation (NM-S).
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NM-S managed the project, designed and performed the experiments, analyzed the data and wrote the manuscript. RI analyzed the ChIP-seq experiment, MD conducted 4T1 LT migration and invasion experiments, and ST performed gene expression analysis and siRNA and cDNA transfection experiments. GC contributed to project management, manuscript assembly and writing.
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Meyer-Schaller, N., Tiede, S., Ivanek, R. et al. A dual role of Irf1 in maintaining epithelial identity but also enabling EMT and metastasis formation of breast cancer cells. Oncogene 39, 4728–4740 (2020). https://doi.org/10.1038/s41388-020-1326-0
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DOI: https://doi.org/10.1038/s41388-020-1326-0
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