title: Paclitaxel treatment of breast cancer cell lines modulates Fas/Fas ligand expression and induces apoptosis which can be inhibited through the CD40 receptor.
abstract: OBJECTIVE
  Cytotoxic chemotherapy of advanced breast cancer is frequently complicated by drug resistance. Our goal was to define the role of the apoptosis-regulating receptors Fas (CD95) and CD40 in the chemosensitivity of breast cancer.
  
  
  METHODS
  The sensitivity of four breast cancer cell lines to paclitaxel and mitoxantrone was evaluated using an ATP-based cell viability assay. After verification of apoptosis by annexin V staining and TUNEL assay, cell lines were characterized regarding their constitutive expression of both surface and soluble (s)Fas (CD95) and Fas ligand (Fas-L). The role of the Fas/Fas-L system and different caspases was assessed by blocking drug-mediated apoptosis with specific antibodies. Finally, the paclitaxel sensitivity of the CD40-negative cell line KS was compared to that of its CD40-positive transfectant KS-CD40.
  
  
  CONCLUSIONS
  While the cytotoxic effect of mitoxantrone did not correlate with Fas expression, the results presented here suggest some involvement of the Fas/Fas-L system in paclitaxel-induced apoptosis. Cell lines with constitutive expression of Fas/sFas demonstrated a higher sensitivity to paclitaxel than Fas-negative cells. Incubation with paclitaxel led to a measurable downregulation of the expression of both soluble and surface Fas receptor in these cells. Interestingly, stimulation of the CD40 receptor inhibited paclitaxel-induced apoptosis in the transfected cell line KS-CD40, suggesting a role of this receptor in the modulation of chemosensitivity.
authors.affiliation: Department of Gynecology, University of Heidelberg, Heidelberg, Germany.
authors.forename: Susanne
authors.initials: S
authors.lastname: Stumm
authors.forename: Anke
authors.initials: A
authors.lastname: Meyer
authors.forename: Matthias
authors.initials: M
authors.lastname: Lindner
authors.forename: Gunter
authors.initials: G
authors.lastname: Bastert
authors.forename: Diethelm
authors.initials: D
authors.lastname: Wallwiener
authors.forename: Brigitte
authors.initials: B
authors.lastname: Gückel
mesh_terms: D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism*; D023201:CD40 Ligand / Q000187:drug effects* / Q000378:metabolism; D045744:Cell Line, Tumor; D004797:Enzyme-Linked Immunosorbent Assay; D053222:Fas Ligand Protein; D005260:Female; D005434:Flow Cytometry; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D008562:Membrane Glycoproteins / Q000187:drug effects* / Q000378:metabolism; D017239:Paclitaxel / Q000494:pharmacology*; D014162:Transfection; D019014:fas Receptor / Q000187:drug effects* / Q000378:metabolism
chemical_list: D000972:Antineoplastic Agents, Phytogenic; C505661:FASLG protein, human; D053222:Fas Ligand Protein; D008562:Membrane Glycoproteins; D019014:fas Receptor; D023201:CD40 Ligand; D017239:Paclitaxel