• Open Access

Signal transduction pathway analysis in desmoid-type fibromatosis: Transforming growth factor–β, COX2 and sex steroid receptors

Authors

  • Nicholas A. Mignemi,

    1. Department of Orthopaedics and Rehabilitation, Vanderbilt Orthopaedic Institute, Nashville, Tennessee, USA
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  • Doha M. Itani,

    1. Department of Pathology, Microbiology and Immunology, Nashville, Tennessee, USA
    Current affiliation:
    1. Department of Pathology, Johns Hopkins Hospital, Baltimore, Maryland, USA
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  • John H. Fasig,

    1. Department of Pathology, Microbiology and Immunology, Nashville, Tennessee, USA
    Current affiliation:
    1. Associated Pathologists, P.C., Brentwood, Tennessee, USA
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  • Vicki L. Keedy,

    1. Department of Medicine, Division of Hematology/Oncology, Nashville, Tennessee, USA
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  • Kenneth R. Hande,

    1. Department of Medicine, Division of Hematology/Oncology, Nashville, Tennessee, USA
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  • Brent W. Whited,

    1. Department of Orthopaedics and Rehabilitation, Vanderbilt Orthopaedic Institute, Nashville, Tennessee, USA
    Current affiliation:
    1. Steindler Orthopaedic Clinic, Iowa City, Iowa, USA
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  • Kelly C. Homlar,

    1. Department of Orthopaedics and Rehabilitation, Vanderbilt Orthopaedic Institute, Nashville, Tennessee, USA
    Current affiliation:
    1. Department of Orthopaedic Surgery, Georgia Health Sciences University, Augusta, Georgia, USA
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  • Hernan Correa,

    1. Department of Pathology, Microbiology and Immunology, Nashville, Tennessee, USA
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  • Cheryl M. Coffin,

    1. Department of Pathology, Microbiology and Immunology, Nashville, Tennessee, USA
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  • Jennifer O. Black,

    1. Department of Pathology, Microbiology and Immunology, Nashville, Tennessee, USA
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  • Yajun Yi,

    1. Department of Medicine, Division of Genetic Medicine, Nashville, Tennessee, USA
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  • Jennifer L. Halpern,

    1. Department of Orthopaedics and Rehabilitation, Vanderbilt Orthopaedic Institute, Nashville, Tennessee, USA
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  • Ginger E. Holt,

    1. Department of Orthopaedics and Rehabilitation, Vanderbilt Orthopaedic Institute, Nashville, Tennessee, USA
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  • Herbert S. Schwartz,

    1. Department of Orthopaedics and Rehabilitation, Vanderbilt Orthopaedic Institute, Nashville, Tennessee, USA
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  • Jonathan G. Schoenecker,

    1. Department of Orthopaedics and Rehabilitation, Vanderbilt Orthopaedic Institute, Nashville, Tennessee, USA
    2. Department of Pathology, Microbiology and Immunology, Nashville, Tennessee, USA
    3. Department of Pharmacology, Vanderbilt University Medical Center, Nashville, Tennessee, USA
    4. Department of Pediatrics, Vanderbilt University Medical Center, Nashville, Tennessee, USA
    5. Department of Vanderbilt Center for Bone Biology, Vanderbilt University Medical Center, Nashville, Tennessee, USA
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  • Justin M. M. Cates

    Corresponding author
    1. Department of Pathology, Microbiology and Immunology, Nashville, Tennessee, USA
    • Department of Orthopaedics and Rehabilitation, Vanderbilt Orthopaedic Institute, Nashville, Tennessee, USA
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To whom correspondence should be addressed.

E-mail: justin.m.cates@vanderbilt.edu

Abstract

Despite reports of sex steroid receptor and COX2 expression in desmoid-type fibromatosis, responses to single agent therapy with anti-estrogens and non-steroidal anti-inflammatory drugs are unpredictable. Perhaps combination pharmacotherapy might be more effective in desmoid tumors that co-express these targets. Clearly, further understanding of the signaling pathways deregulated in desmoid tumors is essential for the development of targeted molecular therapy. Transforming growth factor–β (TGFβ) and bone morphogenetic proteins (BMP) are important regulators of fibroblast proliferation and matrix deposition, but little is known about the TGFβ superfamily in fibromatosis. A tissue microarray representing 27 desmoid tumors was constructed; 14 samples of healing scar and six samples of normal fibrous tissue were included for comparison. Expression of selected receptors and activated downstream transcription factors of TGFβ family signaling pathways, β–catenin, sex steroid hormone receptors and COX2 were assessed using immunohistochemistry; patterns of co–expression were explored via correlational statistical analyses. In addition to β–catenin, immunoreactivity for phosphorylated SMAD2/3 (indicative of active TGFβ signaling) and COX2 was significantly increased in desmoid tumors compared with healing scar and quiescent fibrous tissue. Low levels of phosphorylated SMAD1/5/8 were detected in only a minority of cases. Transforming growth factor–β receptor type 1 and androgen receptor were expressed in both desmoid tumors and scar, but not in fibrous tissue. Estrogen receptor–β was present in all cases studied. Transforming growth factor–β signaling appears to be activated in desmoid-type fibromatosis and phosphorylated SMAD2/3 and COX2 immunoreactivity might be of diagnostic utility in these tumors. Given the frequency of androgen receptor, estrogen receptor–β and COX2 co-expression in desmoid tumors, further assessment of the efficacy of combination pharmacotherapy using hormonal agonists/antagonists together with COX2 inhibitors should be considered.

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