title: TGF-β receptor II loss promotes mammary carcinoma progression by Th17 dependent mechanisms.
abstract: We report that IL-17 significantly increases the secretion of CXCL1 and CXCL5 from mammary carcinoma cells, which is downregulated by TGF-β through the type II TGF-β receptor (TβRII). Carcinoma cells with conditional knockout of TβRII (Tgfbr2(KO)) have enhanced sensitivity to IL-17a in the stimulation of chemokine secretion. During polyoma middle T (PyMT) induced tumor progression, levels of Th17 inducing cytokines TGF-β, IL-6, IL-23 were increased in PyMT/Tgfbr2(KO) tumors, which was associated with an increased number of Th17 cells. IL-17 increased the suppressive function of MDSCs on T cells through the upregulation of Arg, IDO, and COX2. Treatment of PyMT/Tgfbr2(KO) mice with anti-IL-17 Ab decreased carcinoma growth and metastatic burden. Analysis of human breast cancer transcriptome databases showed a strong association between IL-17 gene expression and poor outcome in lymph node positive, estrogen receptor negative or luminal B subtypes suggesting potential therapeutic approaches.
authors.affiliation: Department of Cancer Biology, Vanderbilt University, Nashville, TN 37212, USA.
authors.forename: Sergey V
authors.initials: SV
authors.lastname: Novitskiy
authors.forename: Michael W
authors.initials: MW
authors.lastname: Pickup
authors.forename: Agnieszka E
authors.initials: AE
authors.lastname: Gorska
authors.forename: Philip
authors.initials: P
authors.lastname: Owens
authors.forename: Anna
authors.initials: A
authors.lastname: Chytil
authors.forename: Mary
authors.initials: M
authors.lastname: Aakre
authors.forename: Huiyun
authors.initials: H
authors.lastname: Wu
authors.forename: Yu
authors.initials: Y
authors.lastname: Shyr
authors.forename: Harold L
authors.initials: HL
authors.lastname: Moses
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D019743:Chemokines, CXC / Q000235:genetics / Q000378:metabolism; D051546:Cyclooxygenase 2 / Q000235:genetics / Q000378:metabolism; D018450:Disease Progression; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D020381:Interleukin-17 / Q000235:genetics / Q000378:metabolism*; D008024:Ligands; D008325:Mammary Neoplasms, Experimental / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009000:Monocytes / Q000378:metabolism; D009362:Neoplasm Metastasis; D017346:Protein Serine-Threonine Kinases / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D000077294:Receptor, Transforming Growth Factor-beta Type II; D018125:Receptors, Transforming Growth Factor beta / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D058504:Th17 Cells / Q000378:metabolism*; D059467:Transcriptome; D000509:alpha-Fetoproteins / Q000235:genetics / Q000378:metabolism
chemical_list: D019743:Chemokines, CXC; D020381:Interleukin-17; D008024:Ligands; D018125:Receptors, Transforming Growth Factor beta; D000509:alpha-Fetoproteins; C545206:alpha-fetoprotein related protein, mouse; D051546:Cyclooxygenase 2; D017346:Protein Serine-Threonine Kinases; D000077294:Receptor, Transforming Growth Factor-beta Type II