Journal Article

Signal transduction pathway analysis in desmoid‐type fibromatosis: Transforming growth factor–β, COX 2 and sex steroid receptors

Cates, Justin M. M., Homlar, Kelly C., Hande, Kenneth R., Itani, Doha M., Fasig, John H., Schoenecker, Jonathan G., Schwartz, Herbert S., Yi, Yajun, Correa, Hernan, Keedy, Vicki L., Halpern, Jennifer L., Holt, Ginger E., Black, Jennifer O., Whited, Brent W., Coffin, Cheryl M., Mignemi, Nicholas A.

2012

Overview

Despite reports of sex steroid receptor and COX 2 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 ( TGF β) and bone morphogenetic proteins ( BMP ) are important regulators of fibroblast proliferation and matrix deposition, but little is known about the TGF β 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 TGF β family signaling pathways, β–catenin, sex steroid hormone receptors and COX 2 were assessed using immunohistochemistry; patterns of co–expression were explored via correlational statistical analyses. In addition to β–catenin, immunoreactivity for phosphorylated SMAD 2/3 (indicative of active TGF β signaling) and COX 2 was significantly increased in desmoid tumors compared with healing scar and quiescent fibrous tissue. Low levels of phosphorylated SMAD 1/5/8 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 SMAD 2/3 and COX 2 immunoreactivity might be of diagnostic utility in these tumors. Given the frequency of androgen receptor, estrogen receptor–β and COX 2 co‐expression in desmoid tumors, further assessment of the efficacy of combination pharmacotherapy using hormonal agonists/antagonists together with COX 2 inhibitors should be considered.