IL-13R alpha 2 mediates PNR-induced migration and metastasis in ER alpha-negative breast cancer

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-alpha (ER alpha) in ER alpha-positive breast cancer cell lines and high-level expression of PNR correlates with favorable response of ER alpha-positive breast cancer patients to tamoxifen. Interestingly, gene expression microarray study shows that PNR regulates distinct genes from those regulated by ER alpha, suggesting that PNR could have ER alpha-independent functions. Herein, we investigated the function of PNR in ER alpha-negative breast cancer cells. Our results showed that PNR-induced cell migration and metastasis of ER alpha-negative breast cancer cells both in vitro and in vivo, and the effect was attributed to the upregulation of interleukin (IL)-13R alpha 2, a high-affinity receptor for IL-13 that regulates tumor growth, invasion and metastasis of various human cancers. Mechanistically, PNR activated transcription of IL-13R alpha 2 through direct recruitment to IL-13R alpha 2 promoter. Upon stimulation with IL-13, IL-13R alpha 2 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-13R alpha 2, as the closely related IL-13R alpha 1 was not regulated by PNR. IL-13R alpha 2 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 ERa-negative breast cancer metastasis through activation of IL-13R alpha 2-mediated signaling pathway.