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Fibroblast activation protein-α promotes tumor growth and invasion of breast cancer cells through non-enzymatic functions.

Abstract
Fibroblast activation protein-α (FAP) is a cell surface, serine protease of the post-prolyl peptidase family that is expressed in human breast cancer but not in normal tissues. Previously, we showed that FAP expression increased tumor growth rates in a mouse model of human breast cancer. Here the role of the proteolytic activities of FAP in promoting tumor growth, matrix degradation and invasion was investigated. Mammary fat pads of female SCID mice were inoculated with breast cancer cells that express FAP and the mice treated with normal saline or Val-boroPro (talabostat); Glu-boroPro (PT-630); or 1-[[(3-hydroxy-1-adamantyl)amino]acetyl]-2-cyano-(S)-pyrrolidine (LAF-237) that inhibit prolyl peptidases. Other mice were injected with breast cancer cells expressing a catalytically inactive mutant of FAP and did not receive inhibitor treatment. PT-630 and LAF-237 did not slow growth of tumors produced by any of the three cell lines expressing FAP. Talabostat slightly decreased the growth rates of the FAP-expressing tumors but because PT-630 and LAF-237 did not, the growth retardation was likely not related to the inhibition of FAP or the related post-prolyl peptidase dipeptidyl peptidase IV. Breast cancer cells expressing a catalytically inactive mutant of FAP (FAP(S624A)) also produced tumors that grew rapidly. In vitro studies revealed that cells expressing wild type FAP or FAP(S624A) degrade extracellular matrix (ECM) more extensively, accumulate higher levels of matrix metalloproteinase-9 (MMP-9) in conditioned medium, are more invasive in type I collagen gels, and have altered signaling compared to control transfectants that do not express FAP and form slow growing tumors. We conclude that the proteolytic activity of FAP participates in matrix degradation, but other functions of the protein stimulate increased tumor growth.
AuthorsYan Huang, Avis E Simms, Anna Mazur, Sophie Wang, Noel R León, Barry Jones, Nazneen Aziz, Thomas Kelly
JournalClinical & experimental metastasis (Clin Exp Metastasis) Vol. 28 Issue 6 Pg. 567-79 (Aug 2011) ISSN: 1573-7276 [Electronic] Netherlands
PMID21604185 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • Antigens, Neoplasm
  • Biomarkers, Tumor
  • Membrane Proteins
  • Endopeptidases
  • Dipeptidyl Peptidase 4
  • Serine Endopeptidases
  • fibroblast activation protein alpha
  • Gelatinases
Topics
  • Animals
  • Antigens, Neoplasm (genetics, metabolism)
  • Biomarkers, Tumor (genetics, metabolism)
  • Breast Neoplasms (metabolism, pathology, secondary)
  • Cell Line, Tumor
  • Cell Proliferation
  • Dipeptidyl Peptidase 4 (genetics, metabolism)
  • Endopeptidases
  • Female
  • Gelatinases (genetics, metabolism)
  • Gene Expression Regulation, Neoplastic
  • Humans
  • Membrane Proteins (genetics, metabolism)
  • Mice
  • Mice, Inbred BALB C
  • Neoplasm Invasiveness (genetics, pathology)
  • Neoplasm Metastasis (genetics, pathology)
  • Serine Endopeptidases (genetics, metabolism)

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