A Technical Assessment of the Utility of Reverse Phase Protein Arrays for the Study of the Functional Proteome in Non-microdissected Human Breast Cancers

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• 作者：Bryan T. Hennessy (1) (2) (3)
  Yiling Lu (4)
  Ana Maria Gonzalez-Angulo (3) (4) (5)
  Mark S. Carey (4)
  Simen Myhre (6) (7)
  Zhenlin Ju (8)
  Michael A. Davies (9)
  Wenbin Liu (8)
  Kevin Coombes (8)
  Funda Meric-Bernstam (10)
  Isabelle Bedrosian (10)
  Mollianne McGahren (4)
  Roshan Agarwal (4)
  Fan Zhang (4)
  Jens Overgaard (11)
  Jan Alsner (11)
  Richard M. Neve (12)
  Wen-Lin Kuo (12)
  Joe W. Gray (12)
  Anne-Lise Borresen-Dale (6) (7)
  Gordon B. Mills (3) (4)
  
• 关键词：Functional proteome ; RPPA ; Breast cancer ; Kinase signaling ; Steroid signaling
• 刊名：Clinical Proteomics
• 出版年：2010
• 出版时间：December 2010
• 年：2010
• 卷：6
• 期：4
• 页码：129-151
• 全文大小：1261KB
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• 作者单位：Bryan T. Hennessy (1) (2) (3)
  Yiling Lu (4)
  Ana Maria Gonzalez-Angulo (3) (4) (5)
  Mark S. Carey (4)
  Simen Myhre (6) (7)
  Zhenlin Ju (8)
  Michael A. Davies (9)
  Wenbin Liu (8)
  Kevin Coombes (8)
  Funda Meric-Bernstam (10)
  Isabelle Bedrosian (10)
  Mollianne McGahren (4)
  Roshan Agarwal (4)
  Fan Zhang (4)
  Jens Overgaard (11)
  Jan Alsner (11)
  Richard M. Neve (12)
  Wen-Lin Kuo (12)
  Joe W. Gray (12)
  Anne-Lise Borresen-Dale (6) (7)
  Gordon B. Mills (3) (4)
  
  1. Department of Medical Oncology, Beaumont Hospital, Dublin, Ireland
  2. The University of Texas M. D. Anderson Cancer Center (MDACC), 1515 Holcombe Blvd., Houston, TX, 77030, USA
  3. Kleberg Center for Molecular Markers, The University of Texas M. D. Anderson Cancer Center (MDACC), 1515 Holcombe Blvd., Houston, TX, 77030, USA
  4. Department of Systems Biology, The University of Texas M. D. Anderson Cancer Center (MDACC), 1515 Holcombe Blvd., Houston, TX, 77030, USA
  5. Department of Breast Medical Oncology, The University of Texas M. D. Anderson Cancer Center (MDACC), 1515 Holcombe Blvd., Houston, TX, 77030, USA
  6. Department of Genetics, Institute for Cancer Research, Norwegian Radium Hospital, Rikshospitalet University Hospital, Oslo, Norway
  7. Faculty Division, The Norwegian Radium Hospital, Faculty of Medicine, University of Oslo, Oslo, Norway
  8. Department of Bioinformatics and Computational Biology, The University of Texas M. D. Anderson Cancer Center (MDACC), 1515 Holcombe Blvd., Houston, TX, 77030, USA
  9. Department of Melanoma Medical Oncology, The University of Texas M. D. Anderson Cancer Center (MDACC), 1515 Holcombe Blvd., Houston, TX, 77030, USA
  10. Department of Surgical Oncology, The University of Texas M. D. Anderson Cancer Center (MDACC), 1515 Holcombe Blvd., Houston, TX, 77030, USA
  11. Department of Experimental Clinical Oncology, Aarhus University Hospital, Aarhus, Denmark
  12. Lawrence Berkeley National Laboratory, Berkeley, CA, USA
  
• ISSN：1559-0275

文摘

Introduction The lack of large panels of validated antibodies, tissue handling variability, and intratumoral heterogeneity potentially hamper comprehensive study of the functional proteome in non-microdissected solid tumors. The purpose of this study was to address these concerns and to demonstrate clinical utility for the functional analysis of proteins in non-microdissected breast tumors using reverse phase protein arrays (RPPA). Methods Herein, 82 antibodies that recognize kinase and steroid signaling proteins and effectors were validated for RPPA. Intraslide and interslide coefficients of variability were <15%. Multiple sites in non-microdissected breast tumors were analyzed using RPPA after intervals of up to 24?h on the benchtop at room temperature following surgical resection. Results Twenty-one of 82 total and phosphoproteins demonstrated time-dependent instability at room temperature with most variability occurring at later time points between 6 and 24?h. However, the 82-protein functional proteomic “fingerprint-was robust in most tumors even when maintained at room temperature for 24?h before freezing. In repeat samples from each tumor, intratumoral protein levels were markedly less variable than intertumoral levels. Indeed, an independent analysis of prognostic biomarkers in tissue from multiple tumor sites accurately and reproducibly predicted patient outcomes. Significant correlations were observed between RPPA and immunohistochemistry. However, RPPA demonstrated a superior dynamic range. Classification of 128 breast cancers using RPPA identified six subgroups with markedly different patient outcomes that demonstrated a significant correlation with breast cancer subtypes identified by transcriptional profiling. Conclusion Thus, the robustness of RPPA and stability of the functional proteomic “fingerprint-facilitate the study of the functional proteome in non-microdissected breast tumors.