title: Ankyrin repeat domain 1, ANKRD1, a novel determinant of cisplatin sensitivity expressed in ovarian cancer.
abstract: OBJECTIVE
  The standard of care for ovarian cancer includes platinum-based chemotherapy. It is not possible, however, to predict clinical platinum sensitivity or to design rational strategies to overcome resistance. We used a novel approach to identify altered gene expression associated with high sensitivity to cisplatin, to define novel targets to sensitize tumor cells to platins and ultimately improve the effectiveness of this widely used class of chemotherapeutics.
  
  
  METHODS
  Using differential display PCR, we identified genes differentially expressed in a mutagenized cell line with unusual sensitivity to cisplatin. The most highly differentially expressed gene was selected, and its role in determining cisplatin sensitivity was validated by gene transfection and small interfering RNA (siRNA) approaches, by association of expression levels with cisplatin sensitivity in cell lines, and by association of tumor expression levels with survival in a retrospective cohort of 71 patients with serous ovarian adenocarcinoma.
  
  
  RESULTS
  The most highly differently expressed gene identified was ANKRD1, ankyrin repeat domain 1 (cardiac muscle). ANKRD1 mRNA levels were correlated with platinum sensitivity in cell lines, and most significantly, decreasing ANKRD1 using siRNA increased cisplatin sensitivity >2-fold. ANKRD1 was expressed in the majority of ovarian adenocarcinomas tested (62/71, 87%), and higher tumor levels of ANKRD1 were found in patients with worse outcome (overall survival, P=0.013).
  
  
  CONCLUSIONS
  These findings suggest that ANKRD1, a gene not previously associated with ovarian cancer or with response to chemotherapy, is associated with treatment outcome, and decreasing ANKRD1 expression, or function, is a potential strategy to sensitize tumors to platinum-based drugs.
authors.affiliation: Westmead Institute for Cancer Research, University of Sydney at the Westmead Millennium Institute, Westmead Hospital, Westmead, NSW, Australia.
authors.forename: Lyndee L
authors.initials: LL
authors.lastname: Scurr
authors.forename: Alexander D
authors.initials: AD
authors.lastname: Guminski
authors.forename: Yoke-Eng
authors.initials: YE
authors.lastname: Chiew
authors.forename: Rosemary L
authors.initials: RL
authors.lastname: Balleine
authors.forename: Raghwa
authors.initials: R
authors.lastname: Sharma
authors.forename: Ying
authors.initials: Y
authors.lastname: Lei
authors.forename: Kylie
authors.initials: K
authors.lastname: Pryor
authors.forename: Gerard V
authors.initials: GV
authors.lastname: Wain
authors.forename: Alison
authors.initials: A
authors.lastname: Brand
authors.forename: Karen
authors.initials: K
authors.lastname: Byth
authors.forename: Catherine
authors.initials: C
authors.lastname: Kennedy
authors.forename: Helen
authors.initials: H
authors.lastname: Rizos
authors.forename: Paul R
authors.initials: PR
authors.lastname: Harnett
authors.forename: Anna
authors.initials: A
authors.lastname: deFazio
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy* / Q000235:genetics* / Q000401:mortality; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000595:Amino Acid Sequence; D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use; D016466:CHO Cells; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000627:therapeutic use*; D006224:Cricetinae; D003412:Cricetulus; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D005260:Female; D006801:Humans; D008875:Middle Aged; D008969:Molecular Sequence Data; D009124:Muscle Proteins / Q000235:genetics*; D009687:Nuclear Proteins / Q000235:genetics*; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000235:genetics* / Q000401:mortality; D012097:Repressor Proteins / Q000235:genetics*; D020539:Sequence Analysis, Protein; D016019:Survival Analysis
chemical_list: C491304:ANKRD1 protein, human; D000970:Antineoplastic Agents; D009124:Muscle Proteins; D009687:Nuclear Proteins; D012097:Repressor Proteins; D002945:Cisplatin