Functional proteomic analysis of advanced serous ovarian cancer using reverse phase protein array: TGF-β pathway signaling indicates response to primary chemotherapy

Mark S. Carey, Roshan Agarwal, Blake Gilks, Kenneth Swenerton, Steve Kalloger, Jennifer Santos, Zhenlin Ju, Yiling Lu, Fan Zhang, Kevin R. Coombes, Dianne Miller, David Huntsman, Gordon Mills, Bryan T. Hennessy

Research output: Contribution to journalArticle

52 Citations (Scopus)

Abstract

Purpose: 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. Experimental Design: 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 ≤ 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 β (TGF-β) pathway proteins [c-jun-NH 2-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-β pathway proteins was unlikely because of false discovery (P < 0.007; Bonferroni adjusted). Conclusion: TGF-β 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.

Original languageEnglish (US)
Pages (from-to)2852-2860
Number of pages9
JournalClinical Cancer Research
Volume16
Issue number10
DOIs
StatePublished - May 15 2010
Externally publishedYes

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Protein Array Analysis
Transforming Growth Factors
Proteomics
Ovarian Neoplasms
Drug Therapy
Mitogen-Activated Protein Kinase 9
Proteins
Neoplasms
Epidermal Growth Factor Receptor
Multivariate Analysis
British Columbia
Plasminogen Activator Inhibitor 1
Platinum
Treatment Failure
Gynecology
Disease-Free Survival
Carcinogenesis
Research Design
Logistic Models
Outcome Assessment (Health Care)

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Functional proteomic analysis of advanced serous ovarian cancer using reverse phase protein array : TGF-β pathway signaling indicates response to primary chemotherapy. / Carey, Mark S.; Agarwal, Roshan; Gilks, Blake; Swenerton, Kenneth; Kalloger, Steve; Santos, Jennifer; Ju, Zhenlin; Lu, Yiling; Zhang, Fan; Coombes, Kevin R.; Miller, Dianne; Huntsman, David; Mills, Gordon; Hennessy, Bryan T.

In: Clinical Cancer Research, Vol. 16, No. 10, 15.05.2010, p. 2852-2860.

Research output: Contribution to journalArticle

Carey, MS, Agarwal, R, Gilks, B, Swenerton, K, Kalloger, S, Santos, J, Ju, Z, Lu, Y, Zhang, F, Coombes, KR, Miller, D, Huntsman, D, Mills, G & Hennessy, BT 2010, 'Functional proteomic analysis of advanced serous ovarian cancer using reverse phase protein array: TGF-β pathway signaling indicates response to primary chemotherapy', Clinical Cancer Research, vol. 16, no. 10, pp. 2852-2860. https://doi.org/10.1158/1078-0432.CCR-09-2502
Carey, Mark S. ; Agarwal, Roshan ; Gilks, Blake ; Swenerton, Kenneth ; Kalloger, Steve ; Santos, Jennifer ; Ju, Zhenlin ; Lu, Yiling ; Zhang, Fan ; Coombes, Kevin R. ; Miller, Dianne ; Huntsman, David ; Mills, Gordon ; Hennessy, Bryan T. / Functional proteomic analysis of advanced serous ovarian cancer using reverse phase protein array : TGF-β pathway signaling indicates response to primary chemotherapy. In: Clinical Cancer Research. 2010 ; Vol. 16, No. 10. pp. 2852-2860.
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abstract = "Purpose: 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. Experimental Design: 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 ≤ 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 β (TGF-β) pathway proteins [c-jun-NH 2-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-β pathway proteins was unlikely because of false discovery (P < 0.007; Bonferroni adjusted). Conclusion: TGF-β 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.",
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AU - Swenerton, Kenneth

AU - Kalloger, Steve

AU - Santos, Jennifer

AU - Ju, Zhenlin

AU - Lu, Yiling

AU - Zhang, Fan

AU - Coombes, Kevin R.

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