title: Functional proteomic analysis of advanced serous ovarian cancer using reverse phase protein array: TGF-beta pathway signaling indicates response to primary chemotherapy.
abstract: OBJECTIVE
  Using reverse phase protein array, we measured protein expression associated with response to primary chemotherapy in patients with advanced-stage, high-grade serous ovarian cancer.
  
  
  METHODS
  Tumor samples were obtained from 45 patients with advanced high-grade serous cancers from the Gynecology Tumor Bank at the British Columbia Cancer Agency. Treatment consisted of platinum-based chemotherapy following debulking surgery. Protein lysates were prepared from fresh frozen tumor samples, and 80 validated proteins from signaling pathways implicated in ovarian carcinogenesis were measured by reverse phase protein array. Normalization of Ca-125 by the 3rd cycle of chemotherapy was chosen as the primary outcome measure of chemotherapy response. Logistic regression was used for multivariate analysis to identify protein predictors of Ca-125 normalization and Cox regression to test for the association between protein expression and progression-free survival. A significance level of P<or=0.05 was used.
  
  
  RESULTS
  The mean age at diagnosis was 56.8 years. epidermal growth factor receptor, YKL-40, and several transforming growth factor beta (TGF-beta) pathway proteins [c-jun-NH2-kinase (JNK), JNK phosphorylated at residues 183 and 185, plasminogen activator inhibitor 1, Smad3, TAZ] showed significant associations with Ca-125 normalization on univariate testing. On multivariate analysis, epidermal growth factor receptor (P<0.02), JNK (P<0.01), and Smad3 (P<0.04) were significantly associated with normalization of Ca-125. Contingency table analysis of pathway-classified proteins revealed that the selection of TGF-beta pathway proteins was unlikely because of false discovery (P<0.007; Bonferroni adjusted).
  
  
  CONCLUSIONS
  TGF-beta pathway signaling likely plays an important role as a marker or mediator of chemoresistance in advanced serous ovarian cancer. On this basis, future studies to develop and validate a useful predictor of treatment failure are warranted.
authors.affiliation: Department of Systems Biology, University of Texas M.D. Anderson Cancer Center, Houston, Texas, USA. mark.carey@vch.ca
authors.forename: Mark S
authors.initials: MS
authors.lastname: Carey
authors.forename: Roshan
authors.initials: R
authors.lastname: Agarwal
authors.forename: Blake
authors.initials: B
authors.lastname: Gilks
authors.forename: Kenneth
authors.initials: K
authors.lastname: Swenerton
authors.forename: Steve
authors.initials: S
authors.lastname: Kalloger
authors.forename: Jennifer
authors.initials: J
authors.lastname: Santos
authors.forename: Zhenlin
authors.initials: Z
authors.lastname: Ju
authors.forename: Yiling
authors.initials: Y
authors.lastname: Lu
authors.forename: Fan
authors.initials: F
authors.lastname: Zhang
authors.forename: Kevin R
authors.initials: KR
authors.lastname: Coombes
authors.forename: Dianne
authors.initials: D
authors.lastname: Miller
authors.forename: David
authors.initials: D
authors.lastname: Huntsman
authors.forename: Gordon B
authors.initials: GB
authors.lastname: Mills
authors.forename: Bryan T
authors.initials: BT
authors.lastname: Hennessy
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000627:therapeutic use; D014408:Biomarkers, Tumor / Q000378:metabolism*; D018284:Cystadenocarcinoma, Serous / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism*; D018572:Disease-Free Survival; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D005260:Female; D006801:Humans; D053208:Kaplan-Meier Estimate; D008875:Middle Aged; D010051:Ovarian Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism*; D016016:Proportional Hazards Models; D040081:Protein Array Analysis; D040901:Proteomics; D012680:Sensitivity and Specificity; D015398:Signal Transduction / Q000502:physiology*; D016212:Transforming Growth Factor beta / Q000378:metabolism*; D016896:Treatment Outcome
chemical_list: D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; D016212:Transforming Growth Factor beta
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