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IL-13Rα2 mediates PNR-induced migration and metastasis in ERα-negative breast cancer

Oncogene volume 34, pages 1596–1607 (2015)Cite this article

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Abstract

Emerging evidence has linked photoreceptor cell-specific nuclear receptor (PNR/NR2E3), an orphan nuclear hormone receptor, to human breast cancer. PNR was shown to be a transcriptional activator of estrogen receptor-α (ERα) in ERα-positive breast cancer cell lines and high-level expression of PNR correlates with favorable response of ERα-positive breast cancer patients to tamoxifen. Interestingly, gene expression microarray study shows that PNR regulates distinct genes from those regulated by ERα, suggesting that PNR could have ERα-independent functions. Herein, we investigated the function of PNR in ERα-negative breast cancer cells. Our results showed that PNR-induced cell migration and metastasis of ERα-negative breast cancer cells both in vitro and in vivo, and the effect was attributed to the upregulation of interleukin (IL)-13Rα2, a high-affinity receptor for IL-13 that regulates tumor growth, invasion and metastasis of various human cancers. Mechanistically, PNR activated transcription of IL-13Rα2 through direct recruitment to IL-13Rα2 promoter. Upon stimulation with IL-13, IL-13Rα2 increased the extracellular signal-regulated kinases 1 and 2 phosphorylation, which led to breast cancer migration and metastasis. The IL-13 triggered signal cascade was specific to IL-13Rα2, as the closely related IL-13Rα1 was not regulated by PNR. IL-13Rα2 is a novel tumor antigen that is overexpressed in a variety of solid tumor types. This study presents the first evidence that PNR could promote ERα-negative breast cancer metastasis through activation of IL-13Rα2-mediated signaling pathway.

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Acknowledgements

This project was supported by DOD ERA of HOPE Scholar Award (W81XWYH-11–1–0237) to WX.

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  1. Department of Oncology, McArdle Laboratory for Cancer Research, University of Wisconsin-Madison, Madison, WI, USA

    Z Zhao, L Wang & W Xu

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  1. Z Zhao
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Correspondence to W Xu.

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Zhao, Z., Wang, L. & Xu, W. IL-13Rα2 mediates PNR-induced migration and metastasis in ERα-negative breast cancer. Oncogene 34, 1596–1607 (2015). https://doi.org/10.1038/onc.2014.53

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