title: IL-13Rα2 mediates PNR-induced migration and metastasis in ERα-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-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.
authors.affiliation: Department of Oncology, McArdle Laboratory for Cancer Research, University of Wisconsin-Madison, Madison, WI, USA.
authors.forename: Z
authors.initials: Z
authors.lastname: Zhao
authors.affiliation: Department of Oncology, McArdle Laboratory for Cancer Research, University of Wisconsin-Madison, Madison, WI, USA.
authors.forename: L
authors.initials: L
authors.lastname: Wang
authors.affiliation: Department of Oncology, McArdle Laboratory for Cancer Research, University of Wisconsin-Madison, Madison, WI, USA.
authors.forename: W
authors.initials: W
authors.lastname: Xu
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D045744:Cell Line, Tumor; D047628:Estrogen Receptor alpha / Q000378:metabolism*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D057809:HEK293 Cells; D006801:Humans; D018793:Interleukin-13 / Q000378:metabolism; D053663:Interleukin-13 Receptor alpha2 Subunit / Q000235:genetics* / Q000378:metabolism; D061986:MCF-7 Cells; D051379:Mice; D009362:Neoplasm Metastasis; D009368:Neoplasm Transplantation; D057093:Orphan Nuclear Receptors / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D047628:Estrogen Receptor alpha; D018793:Interleukin-13; D053663:Interleukin-13 Receptor alpha2 Subunit; C403073:NR2E3 protein, human; C485736:Nr2e3 protein, mouse; D057093:Orphan Nuclear Receptors
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