title: Signal transduction pathway analysis in desmoid-type fibromatosis: transforming growth factor-β, COX2 and sex steroid receptors.
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.
authors.affiliation: Department of Orthopaedics and Rehabilitation, Vanderbilt Orthopaedic Institute, Nashville, Tennessee, USA.
authors.forename: Nicholas A
authors.initials: NA
authors.lastname: Mignemi
authors.forename: Doha M
authors.initials: DM
authors.lastname: Itani
authors.forename: John H
authors.initials: JH
authors.lastname: Fasig
authors.forename: Vicki L
authors.initials: VL
authors.lastname: Keedy
authors.forename: Kenneth R
authors.initials: KR
authors.lastname: Hande
authors.forename: Brent W
authors.initials: BW
authors.lastname: Whited
authors.forename: Kelly C
authors.initials: KC
authors.lastname: Homlar
authors.forename: Hernan
authors.initials: H
authors.lastname: Correa
authors.forename: Cheryl M
authors.initials: CM
authors.lastname: Coffin
authors.forename: Jennifer O
authors.initials: JO
authors.lastname: Black
authors.forename: Yajun
authors.initials: Y
authors.lastname: Yi
authors.forename: Jennifer L
authors.initials: JL
authors.lastname: Halpern
authors.forename: Ginger E
authors.initials: GE
authors.lastname: Holt
authors.forename: Herbert S
authors.initials: HS
authors.lastname: Schwartz
authors.forename: Jonathan G
authors.initials: JG
authors.lastname: Schoenecker
authors.forename: Justin M M
authors.initials: JM
authors.lastname: Cates
mesh_terms: D000293:Adolescent; D000328:Adult; D019485:Bone Morphogenetic Proteins / Q000378:metabolism; D002648:Child; D002675:Child, Preschool; D051546:Cyclooxygenase 2 / Q000378:metabolism*; D047629:Estrogen Receptor beta / Q000378:metabolism*; D005260:Female; D018222:Desmoid Tumors / Q000378:metabolism*; D006801:Humans; D007223:Infant; D008297:Male; D008875:Middle Aged; D011944:Receptors, Androgen / Q000378:metabolism*; D015398:Signal Transduction; D051899:Smad2 Protein / Q000235:genetics / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000378:metabolism*; D051176:beta Catenin / Q000378:metabolism
chemical_list: D019485:Bone Morphogenetic Proteins; D047629:Estrogen Receptor beta; D011944:Receptors, Androgen; C497782:SMAD2 protein, human; D051899:Smad2 Protein; D016212:Transforming Growth Factor beta; D051176:beta Catenin; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human