title: Autocrine/paracrine mechanism of interleukin-17B receptor promotes breast tumorigenesis through NF-κB-mediated antiapoptotic pathway.
abstract: Gain of function of membrane receptor was a good strategy exploited by cancer cells to benefit own growth and survival. Overexpression of HER2 has been found to serve as a target for developing trastuzumab to treat 20-25% of breast cancer. However, little or none of the other membrane receptor was found to be useful as a potential target for breast cancer treatment since then. Here, we showed that amplified signaling of interleukin-17 receptor B (IL-17RB) and its ligand IL-17B promoted tumorigenicity in breast cancer cells and impeded acinus formation in immortalized normal mammary epithelial cells. External signal transmitted through IL-17RB activated nuclear factor-κB to upregulate antiapoptotic factor Bcl-2 and induced etoposide resistance. Elevated expression of IL-17RB had a stronger correlation with poor prognosis than HER2 in breast cancer patients. Interestingly, breast cancer patients with high expression of IL-17RB and HER2 had the shortest survival rate. Depletion of IL-17RB in trastuzumab-resistant breast cancer cells significantly reduced their tumorigenic activity, suggesting that IL-17RB and HER2 have an independent role in breast carcinogenesis. Furthermore, treatment with antibodies specifically against IL-17RB or IL-17B effectively attenuated tumorigenicity of breast cancer cells. These results suggest that the amplified IL-17RB/IL-17B signaling pathways may serve as a therapeutic target for developing treatment to manage IL-17RB-associated breast cancer.
authors.affiliation: 1] Institute of Biochemistry and Molecular Biology, College of Medicine, National Taiwan University, Taipei, Taiwan [2] Genomics Research Center, Academia Sinica, Taipei, Taiwan.
authors.forename: C-K
authors.initials: CK
authors.lastname: Huang
authors.affiliation: Genomics Research Center, Academia Sinica, Taipei, Taiwan.
authors.forename: C-Y
authors.initials: CY
authors.lastname: Yang
authors.affiliation: Department of Pathology, National Taiwan University Hospital, Taipei, Taiwan.
authors.forename: Y-M
authors.initials: YM
authors.lastname: Jeng
authors.affiliation: Genomics Research Center, Academia Sinica, Taipei, Taiwan.
authors.forename: C-L
authors.initials: CL
authors.lastname: Chen
authors.affiliation: Genomics Research Center, Academia Sinica, Taipei, Taiwan.
authors.forename: H-H
authors.initials: HH
authors.lastname: Wu
authors.affiliation: Genomics Research Center, Academia Sinica, Taipei, Taiwan.
authors.forename: Y-C
authors.initials: YC
authors.lastname: Chang
authors.affiliation: Genomics Research Center, Academia Sinica, Taipei, Taiwan.
authors.forename: C
authors.initials: C
authors.lastname: Ma
authors.affiliation: Department of Surgery, National Taiwan University Hospital, Taipei, Taiwan.
authors.forename: W-H
authors.initials: WH
authors.lastname: Kuo
authors.affiliation: 1] Department of Surgery, National Taiwan University Hospital, Taipei, Taiwan [2] Cheng Chin General Hospital, Taichung, Taiwan.
authors.forename: K-J
authors.initials: KJ
authors.lastname: Chang
authors.affiliation: 1] Institute of Biochemistry and Molecular Biology, College of Medicine, National Taiwan University, Taipei, Taiwan [2] Genomics Research Center, Academia Sinica, Taipei, Taiwan.
authors.forename: J-Y
authors.initials: JY
authors.lastname: Shew
authors.affiliation: 1] Institute of Biochemistry and Molecular Biology, College of Medicine, National Taiwan University, Taipei, Taiwan [2] Genomics Research Center, Academia Sinica, Taipei, Taiwan [3] Department of Biological Chemistry, University of California, Irvine, CA, USA.
authors.forename: W-H
authors.initials: WH
authors.lastname: Lee
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D019898:Autocrine Communication; D001943:Breast Neoplasms / Q000378:metabolism / Q000473:pathology*; D063646:Carcinogenesis / Q000187:drug effects; D045744:Cell Line, Tumor; D005047:Etoposide / Q000494:pharmacology; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D020381:Interleukin-17 / Q000276:immunology / Q000378:metabolism; D061986:MCF-7 Cells; D008325:Mammary Neoplasms, Experimental; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000378:metabolism*; D019899:Paracrine Communication; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism; D053722:Receptors, Interleukin-17 / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: D005047:Etoposide; D020381:Interleukin-17; D016328:NF-kappa B; D018719:Erb-b2 Receptor Tyrosine Kinases; D053722:Receptors, Interleukin-17