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

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

SUBMITTER: Zhao Z 

PROVIDER: S-EPMC4321963 | biostudies-literature | 2015 Mar

REPOSITORIES: biostudies-literature