title: The effects of physiological estrogen concentration on the immune response of urothelial carcinoma cells to bacillus Calmette-Guérin.
abstract: OBJECTIVE
  Meta-analysis has shown that bacillus Calmette-Guérin is less effective in females undergoing treatment for urothelial carcinoma. Urothelial carcinoma cells express immune regulatory proteins as a consequence of bacillus Calmette-Guérin induced, nuclear factor κB signaling. Nuclear factor κB is influenced by estrogen receptor binding. We evaluated the effect of the physiological estradiol concentration on the expression of bacillus Calmette-Guérin induced, nuclear factor κB regulated immune proteins.
  
  
  METHODS
  We determined the estrogen receptor expression status of human urothelial carcinoma cell lines by reverse transcriptase-polymerase chain reaction. The functional status of estrogen receptor signaling was established using estrogen receptor reporter constructs. We used gene expression profiling of urothelial carcinoma cells combined with reverse transcriptase-polymerase chain reaction to identify the nuclear factor κB dependent immune regulatory proteins expressed in response to bacillus Calmette-Guérin. We determined the influence of the estradiol concentration on bacillus Calmette-Guérin dependent interleukin-6 and 8, chemokine (c-x-c motif) ligands 1 and 2, and chemokine (c-c motif) ligand 20 gene expression by quantitative reverse transcriptase-polymerase chain reaction.
  
  
  RESULTS
  Urothelial carcinoma cell lines expressed functional estrogen receptor. Nuclear factor κB signaling was inhibited by estradiol in a dose and estrogen receptor dependent manner. Urothelial carcinoma cell expression of interleukin-6 and 8, chemokine (c-x-c motif) ligands 1 and 2, and chemokine (c-c motif) ligand 20 was up-regulated in response to bacillus Calmette-Guérin in a nuclear factor κB dependent manner. There was a significant dose dependent effect of estradiol on the expression of these genes in bacillus Calmette-Guérin treated urothelial carcinoma cells.
  
  
  CONCLUSIONS
  The physiological concentration of estrogen influences nuclear factor κB signaling and bacillus Calmette-Guérin dependent gene expression. Serum estradiol fluctuations in women may influence the response of urothelial carcinoma to intravesical bacillus Calmette-Guérin treatment.
authors.affiliation: Medical College of Wisconsin, Milwaukee, Wisconsin, USA.
authors.forename: Amy I
authors.initials: AI
authors.lastname: Guise
authors.forename: Fanghong
authors.initials: F
authors.lastname: Chen
authors.forename: Guangjian
authors.initials: G
authors.lastname: Zhang
authors.forename: William
authors.initials: W
authors.lastname: See
mesh_terms: D000276:Adjuvants, Immunologic / Q000494:pharmacology*; D001500:BCG Vaccine / Q000494:pharmacology*; D002295:Carcinoma, Transitional Cell / Q000276:immunology* / Q000378:metabolism*; D004967:Estrogens / Q000096:biosynthesis / Q000502:physiology*; D006801:Humans; D016328:NF-kappa B / Q000502:physiology*; D014407:Tumor Cells, Cultured; D014571:Urologic Neoplasms / Q000276:immunology* / Q000378:metabolism*
chemical_list: D000276:Adjuvants, Immunologic; D001500:BCG Vaccine; D004967:Estrogens; D016328:NF-kappa B