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Estrogen Signaling Is Active in Cartilaginous Tumors: Implications for Antiestrogen Therapy as Treatment Option of Metastasized or Irresectable Chondrosarcoma

Authors' Affiliations: Departments of ¹ Pathology, ² Endocrinology, and ³ Pediatrics, Leiden University Medical Centre, Leiden, the Netherlands

Requests for reprints: Anne-Marie Cleton-Jansen, Department of Pathology, Leiden University Medical Centre, P.O. Box 9600, L1-Q, 2300 RC Leiden, the Netherlands. Phone: 31-71-5266515; Fax: 31-71-5248158; E-mail: A.M.Cleton-Jansen{at}lumc.nl.

Purpose: Chondrosarcoma is a malignant cartilaginous matrix–producing tumor that can be lethal in 10% to 50% of the patients. Surgery is the only effective treatment known as these tumors are notorious refractory to all types of conventional chemotherapy or radiotherapy. To identify a target for therapy, we want to determine whether estrogen signaling is active in chondrosarcoma because estrogen is important in the regulation of longitudinal growth that is initiated by chondrocyte proliferation and differentiation in the epiphyseal growth plate of long bones.

Experimental Design: We studied protein expression of the estrogen receptor in 35 cartilaginous tumors as well as mRNA levels for the estrogen receptor and for aromatase, an enzyme for estrogen synthesis and another potential therapeutic target. Furthermore, the activity of aromatase was determined in vitro by the tritiated water release assay. Dose-response experiments with chondrosarcoma cultured cells were done with estrogen, androstenedione, and exemestane.

Results: All chondrosarcomas tested showed mRNA and nuclear protein expression of the estrogen receptor. Also, aromatase mRNA was detected. The aromatase activity assay showed a functional aromatase enzyme in primary chondrosarcoma cultures and in a cell line. Growth of chondrosarcoma cell cultures can be stimulated by adding estrogen or androstenedione, which can be inhibited by exemestane.

Conclusions: These results show, on the RNA, protein, and cell biological levels, that the ligand and the receptor are active in estrogen-mediated signal transduction. This observation implicates potential use of targeted drugs that interfere with estrogen signaling, such as those applied for treating breast cancer.

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