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Insulin-like Growth Factor Binding Proteins IGFBP3, IGFBP4, and IGFBP5 Predict Endocrine Responsiveness in Patients with Ovarian Cancer

Authors' Affiliations: ¹ Edinburgh Cancer Research Center and ² Department of Pathology, University of Edinburgh, Edinburgh, United Kingdom

Requests for reprints: Simon Langdon, Edinburgh Cancer Research Center, University of Edinburgh, Crewe Road South, Edinburgh, EH4 2XR, United Kingdom. Phone: 44-1317773537; Fax: 44-1317773520; E-mail: simon.langdon{at}cancer.org.uk.

Purpose: This study sought to explore the predictive value of the insulin-like growth factor (IGF) binding proteins (IGFBP) as markers of response in ovarian cancer patients treated with the aromatase inhibitor letrozole.

Experimental Design: IGFBP mRNA expression in cell lines was measured by quantitative reverse transcription-PCR and IGFBP protein expression measured in sections from primary tumors of patients treated with letrozole by semiquantitative immunohistochemistry.

Results: Quantitative reverse transcription-PCR analysis showed that IGFBP3 and IGFBP5 were down-regulated and IGFBP4 was up-regulated by 17ß-estradiol (E₂) in an estrogen receptor (ER)–positive ovarian cancer cell line. Expressions of IGFBP1, IGFBP2, and IGFBP6 were unaffected by E₂. The E₂ modulation of these genes was reversed by tamoxifen. Using ER-specific (propyl pyrazole triol) and ERß-specific (diarylpropionitrile) agonists, the gene expression modulations produced by E₂ could be replicated by propyl pyrazole triol but not by diarylpropionitrile.

For ovarian cancer patients being treated with letrozole, we tested the predictive value of the IGFBPs in paraffin-fixed sections from their primary tumors by semiquantitative immunohistochemistry. Using serum CA125 as an indicator of progression/response, significant differences in expression levels of IGFBPs were observed between tumors from CA125 responding/stable patients compared with tumors from progressing patients. Mean immunoscores for IGFBP3 and IGFBP5 were significantly lower, and mean expression of IGFBP4 was significantly higher in tumors from patients demonstrating CA125 response or stabilization compared with CA125 progression.

Conclusion: These results indicate that expression levels of certain IGFBP family members in ovarian cancers are estrogen regulated and can, thus, help identify patients who could benefit from endocrine therapy.