title: Changes in the transcriptome of the human endometrial Ishikawa cancer cell line induced by estrogen, progesterone, tamoxifen, and mifepristone (RU486) as detected by RNA-sequencing.
abstract: BACKGROUND
  Estrogen (E2) and progesterone (P4) are key players in the maturation of the human endometrium. The corresponding steroid hormone modulators, tamoxifen (TAM) and mifepristone (RU486) are widely used in breast cancer therapy and for contraception purposes, respectively.
  
  
  RESULTS
  Gene expression profiling of the human endometrial Ishikawa cancer cell line treated with E2 and P4 for 3 h and 12 h, and TAM and RU486 for 12 h, was performed using RNA-sequencing. High levels of mRNA were detected for genes, including PSAP, ATP5G2, ATP5H, and GNB2L1 following E2 or P4 treatment. A total of 82 biomarkers for endometrial biology were identified among E2 induced genes, and 93 among P4 responsive genes. Identified biomarkers included: EZH2, MDK, MUC1, SLIT2, and IL6ST, which are genes previously associated with endometrial receptivity. Moreover, 98.8% and 98.6% of E2 and P4 responsive genes in Ishikawa cells, respectively, were also detected in two human mid-secretory endometrial biopsy samples. TAM treatment exhibited both antagonistic and agonistic effects of E2, and also regulated a subset of genes independently. The cell cycle regulator cyclin D1 (CCND1) showed significant up-regulation following treatment with TAM. RU486 did not appear to act as a pure antagonist of P4 and a functional analysis of RU486 response identified genes related to adhesion and apoptosis, including down-regulated genes associated with cell-cell contacts and adhesion as CTNND1, JUP, CDH2, IQGAP1, and COL2A1.
  
  
  CONCLUSIONS
  Significant changes in gene expression by the Ishikawa cell line were detected after treatments with E2, P4, TAM, and RU486. These transcriptome data provide valuable insight into potential biomarkers related to endometrial receptivity, and also facilitate an understanding of the molecular changes that take place in the endometrium in the early stages of breast cancer treatment and contraception usage.
authors.affiliation: Centre for Biology of Integrated Systems, Tallinn University of Technology, Tallinn, Estonia. karin.tamm@ttu.ee
authors.forename: Karin
authors.initials: K
authors.lastname: Tamm-Rosenstein
authors.forename: Jaak
authors.initials: J
authors.lastname: Simm
authors.forename: Marina
authors.initials: M
authors.lastname: Suhorutshenko
authors.forename: Andres
authors.initials: A
authors.lastname: Salumets
authors.forename: Madis
authors.initials: M
authors.lastname: Metsis
mesh_terms: D045744:Cell Line, Tumor; D016889:Endometrial Neoplasms / Q000235:genetics*; D004967:Estrogens / Q000494:pharmacology*; D005260:Female; D019204:GTP-Binding Proteins / Q000235:genetics; D020869:Gene Expression Profiling; D006801:Humans; D008565:Membrane Proteins / Q000235:genetics; D015735:Mifepristone / Q000494:pharmacology*; D024101:Mitochondrial Proteins / Q000235:genetics; D009363:Neoplasm Proteins / Q000235:genetics; D011374:Progesterone / Q000494:pharmacology*; D000075370:Receptors for Activated C Kinase; D011956:Receptors, Cell Surface / Q000235:genetics; D013629:Tamoxifen / Q000494:pharmacology*; D059467:Transcriptome / Q000187:drug effects / Q000235:genetics*
chemical_list: D004967:Estrogens; C402222:MTCH1 protein, human; D008565:Membrane Proteins; D024101:Mitochondrial Proteins; D009363:Neoplasm Proteins; C419368:RACK1 protein, human; D000075370:Receptors for Activated C Kinase; D011956:Receptors, Cell Surface; D013629:Tamoxifen; D015735:Mifepristone; D011374:Progesterone; D019204:GTP-Binding Proteins