title: Increased expression of transcription factor TFAP2α correlates with chemosensitivity in advanced bladder cancer.
abstract: BACKGROUND
  The standard treatment for patients with advanced transitional cell carcinoma of the bladder is platin based chemotherapy. Only approximately 50% of the patients respond to chemotherapy. Therefore, molecular predictive markers for identification of chemotherapy sensitive subgroups of patients are highly needed. We selected the transcription factor TFAP2α from a previously identified gene expression signature for chemotherapy response.
  
  
  METHODS
  TFAP2α expression and localization was assessed by immunohistochemistry using a tissue microarray (TMA) containing 282 bladder cancer tumors from patients with locally advanced (pT2-T4(b) and N(1-3)) or metastatic (M(1)) disease. All patients had received cisplatin containing chemotherapy. Furthermore, QPCR analysis of three TFAP2α isoforms was performed on tumor specimens of advanced muscle invasive bladder cancers (T2-4). Using the bladder cell lines T24 and SW780 the relation of TFAP2α and cisplatin and gemcitabine sensitivity as well as cell proliferation was examined using siRNA directed TFAP2α knockdown.
  
  
  RESULTS
  TFAP2α protein expression was analyzed on a TMA with cores from 282 advanced bladder cancer tumors from patients treated with cisplatin based combinational chemotherapy. TFAP2α was identified as a strong independent predictive marker for a good response and survival after cisplatin-containing chemotherapy in patients with advanced bladder cancer. Strong TFAP2α nuclear and cytoplasmic staining predicted good response to chemotherapy in patients with lymph node metastasis, whereas weak TFAP2α nuclear staining predicted good response in patients without lymph node metastasis. In vitro studies showed that siRNA mediated knockdown of TFAP2α increased the proliferation of SW780 cells and rendered the cells less sensitive to cisplatin and gemcitabine. In contrast to that T24 bladder cells with mutated p53 showed to be more drug sensitive upon TFAP2α depletion.
  
  
  CONCLUSIONS
  High levels of nuclear and cytoplasmic TFAP2α protein were a predictor of increased overall survival and progression free survival in patients with advanced bladder cancer treated with cisplatin based chemotherapy. TFAP2α knockdown increased the proliferation of the SW780 bladder cells and reduced cisplatin and gemcitabine induced cell death. The inverse effect was observed in the TP53 mutated T24 cell line where TFAP2α silencing augmented cisplatin and gemcitabine sensitivity and did not stimulate proliferation.
authors.affiliation: Molecular Diagnostic Laboratory, Department of Molecular Medicine, Aarhus University Hospital, Aarhus, Denmark. iver.nordentoft@ki.au.dk
authors.forename: Iver
authors.initials: I
authors.lastname: Nordentoft
authors.forename: Lars
authors.initials: L
authors.lastname: Dyrskjøt
authors.forename: Julie S
authors.initials: JS
authors.lastname: Bødker
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Wild
authors.forename: Arndt
authors.initials: A
authors.lastname: Hartmann
authors.forename: Simone
authors.initials: S
authors.lastname: Bertz
authors.forename: Jan
authors.initials: J
authors.lastname: Lehmann
authors.forename: Torben F
authors.initials: TF
authors.lastname: Orntoft
authors.forename: Karin
authors.initials: K
authors.lastname: Birkenkamp-Demtroder
mesh_terms: D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology / Q000627:therapeutic use; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism; D019556:COS Cells; D002277:Carcinoma / Q000188:drug therapy / Q000401:mortality / Q000503:physiopathology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002522:Chlorocebus aethiops; D002945:Cisplatin / Q000494:pharmacology / Q000627:therapeutic use; D003841:Deoxycytidine / Q000031:analogs & derivatives / Q000494:pharmacology / Q000627:therapeutic use; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D055785:Gene Knockdown Techniques; D006801:Humans; D009367:Neoplasm Staging; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D016019:Survival Analysis; D050656:Transcription Factor AP-2 / Q000235:genetics / Q000378:metabolism*; D001749:Urinary Bladder Neoplasms / Q000188:drug therapy / Q000401:mortality / Q000503:physiopathology*; D000093542:Gemcitabine
chemical_list: D000964:Antimetabolites, Antineoplastic; D014408:Biomarkers, Tumor; D020033:Protein Isoforms; C493673:TFAP2A protein, human; D050656:Transcription Factor AP-2; D003841:Deoxycytidine; D002945:Cisplatin; D000093542:Gemcitabine