title: Molecular characterisation of isogenic taxane resistant cell lines identify novel drivers of drug resistance.
abstract: BACKGROUND
  Taxanes such as paclitaxel and docetaxel are used successfully to treat breast cancer, usually in combination with other agents. They interfere with microtubules causing cell cycle arrest; however, the mechanisms underlying the clinical effects of taxanes are yet to be fully elucidated.
  
  
  METHODS
  Isogenic paclitaxel resistant (PACR) MDA‒MB‒231, paclitaxel resistant ZR75‒1 and docetaxel resistant (DOCR) ZR75‒1 cell lines were generated by incrementally increasing taxane dose in native cell lines in vitro. We used aCGH analysis to identify mechanisms driving taxane resistance.
  
  
  RESULTS
  Taxane resistant cell lines exhibited an 18-170 fold increased resistance to taxanes, with the ZR75-1 resistant cell lines also demonstrating cross resistance to anthracyclines. Paclitaxel treatment of native cells resulted in a G2/M block and a decrease in the G1 phase of the cell cycle. However, in the resistant cell lines, minimal changes were present. Functional network analysis revealed that the mitotic prometaphase was lost in the resistant cell lines.
  
  
  CONCLUSIONS
  This study established a model system for examining taxane resistance and demonstrated that both MDR and mitosis represent common mechanism of taxane resistance.
authors.forename: Juliet
authors.initials: J
authors.lastname: Kenicer
authors.forename: Melanie
authors.initials: M
authors.lastname: Spears
authors.forename: Nicola
authors.initials: N
authors.lastname: Lyttle
authors.forename: Karen J
authors.initials: KJ
authors.lastname: Taylor
authors.forename: Linda
authors.initials: L
authors.lastname: Liao
authors.forename: Carrie A
authors.initials: CA
authors.lastname: Cunningham
authors.forename: Maryou
authors.initials: M
authors.lastname: Lambros
authors.forename: Alan
authors.initials: A
authors.lastname: MacKay
authors.forename: Cindy
authors.initials: C
authors.lastname: Yao
authors.forename: Jorge
authors.initials: J
authors.lastname: Reis-Filho
authors.affiliation: Biomarkers and Companion Diagnostics, Edinburgh Cancer Research Centre, Crewe Road South, Edinburgh EH4 2XR, UK. John.Bartlett@oicr.on.ca.
authors.forename: John M S
authors.initials: JM
authors.lastname: Bartlett
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B / Q000235:genetics / Q000378:metabolism; D000970:Antineoplastic Agents / Q000494:pharmacology*; D045744:Cell Line, Tumor; D055028:Comparative Genomic Hybridization; D000077143:Docetaxel; D018432:Drug Resistance, Multiple; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D015870:Gene Expression; D006801:Humans; D020128:Inhibitory Concentration 50; D017239:Paclitaxel / Q000494:pharmacology*; D043823:Taxoids / Q000494:pharmacology*
chemical_list: C513055:ABCB1 protein, human; D018435:ATP Binding Cassette Transporter, Subfamily B; D000970:Antineoplastic Agents; D043823:Taxoids; D000077143:Docetaxel; D017239:Paclitaxel