title: The role of Tyk2 in regulation of breast cancer growth.
abstract: The antigrowth and immunomodulatory actions of interferons (IFNs) have enabled these cytokines to be used therapeutically for the treatment of a variety of hematologic and solid malignancies. IFNs exert their effects by activation of the Jak/Stat signaling pathway. IFNγ stimulates the tyrosine kinases Jak1 and Jak2, resulting in activation of the Stat1 transcription factor, whereas type 1 IFNs (IFNα/β) activate Jak1 and Tyk2, which mediate their effects through Stat1 and Stat2. Disruption in the expression of IFNγ, IFNα receptors, or Stat1 inhibits antitumor responses and blunt cancer immunosurveillance in mice. Mutations in Jak2 or constitutive activation of Jak1 or Jak2 also promote the development of a variety of malignancies. Although there are data indicating that Tyk2 plays a role in the pathogenesis of lymphomas, the effects of Tyk2 expression on tumorigenesis are unknown. We report here that Tyk2(-/-) mice inoculated with 4T1 breast cancer cells show enhanced tumor growth and metastasis compared to Tyk2(+/+) animals. Accelerated growth of 4T1 cells in Tyk2(-/-) animals does not appear to be due to decreased function of CD4(+), CD8(+) T cells, or NK cells. Rather, the tumor suppresive effects of Tyk2 are mediated at least in part by myeloid-derived suppressor cells, which appear to be more effective in inhibiting T cell responses in Tyk2(-/-) mice. Our results provide the first evidence for a role of Tyk2 in suppressing the growth and metastasis of breast cancer.
authors.affiliation: Department of Biochemistry and Molecular Biology, Virginia Commonwealth University, Richmond, Virginia 23298, USA.
authors.forename: Qifang
authors.initials: Q
authors.lastname: Zhang
authors.forename: Jamie L
authors.initials: JL
authors.lastname: Sturgill
authors.forename: Maciej
authors.initials: M
authors.lastname: Kmieciak
authors.forename: Karol
authors.initials: K
authors.lastname: Szczepanek
authors.forename: Marta
authors.initials: M
authors.lastname: Derecka
authors.forename: Catherine
authors.initials: C
authors.lastname: Koebel
authors.forename: Laura J
authors.initials: LJ
authors.lastname: Graham
authors.forename: Yun
authors.initials: Y
authors.lastname: Dai
authors.forename: Shuang
authors.initials: S
authors.lastname: Chen
authors.forename: Steven
authors.initials: S
authors.lastname: Grant
authors.forename: Joanna
authors.initials: J
authors.lastname: Cichy
authors.forename: Kazuya
authors.initials: K
authors.lastname: Shimoda
authors.forename: Ana
authors.initials: A
authors.lastname: Gamero
authors.forename: Masoud
authors.initials: M
authors.lastname: Manjili
authors.forename: Harry
authors.initials: H
authors.lastname: Bear
authors.forename: Daniel
authors.initials: D
authors.lastname: Conrad
authors.forename: Andrew C
authors.initials: AC
authors.lastname: Larner
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D005260:Female; D008325:Mammary Neoplasms, Experimental / Q000378:metabolism* / Q000473:pathology / Q000556:secondary; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D053634:TYK2 Kinase / Q000172:deficiency / Q000378:metabolism*
chemical_list: D053634:TYK2 Kinase; C499356:Tyk2 protein, mouse