title: Stat3 mediates expression of autotaxin in breast cancer.
abstract: We determined that signal transducer and activator of transcription 3 (Stat3) is tyrosine phosphorylated in 37% of primary breast tumors and 63% of paired metastatic axillary lymph nodes. Examination of the distribution of tyrosine phosphorylated (pStat3) in primary tumors revealed heterogenous expression within the tumor with the highest levels found in cells on the edge of tumors with relatively lower levels in the central portion of tumors. In order to determine Stat3 target genes that may be involved in migration and metastasis, we identified those genes that were differentially expressed in primary breast cancer samples as a function of pStat3 levels. In addition to known Stat3 transcriptional targets (Twist, Snail, Tenascin-C and IL-8), we identified ENPP2 as a novel Stat3 regulated gene, which encodes autotaxin (ATX), a secreted lysophospholipase which mediates mammary tumorigenesis and cancer cell migration. A positive correlation between nuclear pStat3 and ATX was determined by immunohistochemical analysis of primary breast cancer samples and matched axillary lymph nodes and in several breast cancer derived cell lines. Inhibition of pStat3 or reducing Stat3 expression led to a decrease in ATX levels and cell migration. An association between Stat3 and the ATX promoter, which contains a number of putative Stat3 binding sites, was determined by chromatin immunoprecipitation. These observations suggest that activated Stat3 may regulate the migration of breast cancer cells through the regulation of ATX.
authors.affiliation: Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York, United States of America.
authors.forename: Janeen
authors.initials: J
authors.lastname: Azare
authors.forename: Ashley
authors.initials: A
authors.lastname: Doane
authors.forename: Kenneth
authors.initials: K
authors.lastname: Leslie
authors.forename: Qing
authors.initials: Q
authors.lastname: Chang
authors.forename: Marjan
authors.initials: M
authors.lastname: Berishaj
authors.forename: Jennifer
authors.initials: J
authors.lastname: Nnoli
authors.forename: Kevin
authors.initials: K
authors.lastname: Mark
authors.forename: Hikmat
authors.initials: H
authors.lastname: Al-Ahmadie
authors.forename: William
authors.initials: W
authors.lastname: Gerald
authors.forename: Maryam
authors.initials: M
authors.lastname: Hassimi
authors.forename: Agnes
authors.initials: A
authors.lastname: Viale
authors.forename: Mary
authors.initials: M
authors.lastname: Stracke
authors.forename: David
authors.initials: D
authors.lastname: Lyden
authors.forename: Jacqueline
authors.initials: J
authors.lastname: Bromberg
mesh_terms: D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D016000:Cluster Analysis; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D052138:Genes, Neoplasm / Q000235:genetics; D006801:Humans; D008198:Lymph Nodes / Q000378:metabolism / Q000473:pathology; D009362:Neoplasm Metastasis; D010727:Phosphoric Diester Hydrolases / Q000378:metabolism*; D010766:Phosphorylation; D019000:Phosphotyrosine / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000378:metabolism*; D000099189:Lysophospholipase D
chemical_list: D010727:Phosphoric Diester Hydrolases; D019000:Phosphotyrosine; D050796:STAT3 Transcription Factor; D000099189:Lysophospholipase D; C494086:STAT3 protein, human