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Carcinoma and stromal enzyme activity profiles associated with breast tumor growth in vivo

Academic Article
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Overview

related to degree

  • Niessen, Sherry, Ph.D. in Chemistry, Scripps Research 2004 - 2008
  • Jessani, Nadim, Ph.D. in Biology, Scripps Research 1998 - 2004

authors

  • Jessani, Nadim
  • Humphrey, M.
  • McDonald, W. H.
  • Niessen, Sherry
  • Masuda, K.
  • Gangadharan, B.
  • Yates III, John
  • Mueller, B. M.
  • Cravatt, Benjamin

publication date

  • September 2004

journal

  • Proceedings of the National Academy of Sciences of the United States of America  Journal

abstract

  • Cancer research depends on the use of human cell lines for both the in vitro (culture) and in vivo (xenograft) analysis of tumor progression and treatment. However, the extent to which cultured preparations of human cancer lines display similar properties in vivo, where important host factors may influence tumor biology, remains unclear. Here, we address this question by conducting a functional proteomic analysis of the human breast cancer line MDA-MB-231 grown in culture and as orthotopic xenograft tumors in the mammary fad pad of immunodeficient mice. Using a suite of activity-based chemical probes, we identified carcinoma (human) enzyme activities that were expressed selectively in culture or in xenograft tumors. Likewise, distinct groups of stromal (mouse) enzyme activities were found that either infiltrated or were excluded from xenograft tumors, indicating a contribution by specific host components to breast cancer development. MDA-MB-231 cells isolated from tumors exhibited profound differences in their enzyme activity profiles compared with the parent cell line, including the dramatic posttranscriptional up-regulation of the serine proteases urokinase plasminogen activator and tissue plasminogen activator and down-regulation of the glycolytic enzyme phosphofructokinase. These altered enzyme activity profiles correlated with significantly greater tumor growth rates and metastases for xenograft-derived MDA-MB-231 cells upon reintroduction into mice. Collectively, these data indicate that the in vivo environment of the mouse mammary fat pad cultivates the growth of human breast cancer cells with elevated tumorigenic properties and highlight the value of activity-based protein profiling for identifying proteomic signatures that depict such changes in cancer cell biology.

subject areas

  • Amino Acid Sequence
  • Animals
  • Breast Neoplasms
  • Cell Line, Tumor
  • Consensus Sequence
  • Female
  • Humans
  • Mice
  • Mice, SCID
  • Neoplasm Transplantation
  • Peptide Fragments
  • Peptide Hydrolases
  • Peptide-N4-(N-acetyl-beta-glucosaminyl) Asparagine Amidase
  • Proteome
  • Stromal Cells
  • Transplantation, Heterologous
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Identity

PubMed Central ID

  • PMC518829

International Standard Serial Number (ISSN)

  • 0027-8424

Digital Object Identifier (DOI)

  • 10.1073/pnas.0404727101

PubMed ID

  • 15356343
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Additional Document Info

start page

  • 13756

end page

  • 13761

volume

  • 101

issue

  • 38

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