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

Abstract

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 17h-estradiol (E 2 ) in an estrogen receptor (ER)^positive ovarian cancer cell line. Expressions of IGFBP1, IGFBP2, and IGFBP6 were unaffected by E 2 . The E 2 modulation of these genes was reversed by tamoxifen. Using ERa-specific (propyl pyrazole triol) and ERh-specific (diarylpropionitrile) agonists, the gene expression modulations produced by E 2 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.

Targeting the insulin-like growth factor receptor pathway in lung cancer: problems and pitfalls

“…Similar prognostic significance of IGFBPs was also recently recorded for early stage, surgically resected NSCLC [Shersher et al 2011]. The intricacies of the IGF-independent action of IGFBPs are beyond the scope of this review but have been described in several cancer models [Chang et al 2002;Dunlap et al 2007;Firth and Baxter, 2002;Hoeflich et al 2001;Li et al 2010;Migita et al 2010;Sureshbabu et al 2009;Walker et al 2007;Wolpin et al 2007].…”

Circulating IGF system and treatment outcome in epithelial ovarian cancer

“…Recent studies have shown that, in EOC tissues, decreased concentrations of IGFBP3 were significantly associated with advanced stage, suboptimal cytoreduction, and an elevated risk of progression (Katsaros et al 2001, Lu et al 2006, Torng et al 2008. In contrast, one study demonstrated the opposite findings (Walker et al 2007). Accumulating evidence supports the idea that IGFBP2 might act as a promoter, rather than a tumor suppressor, in EOC.…”

Endocrine therapy in epithelial ovarian cancer

“…One interesting family of proteins that emerged was the insulin-like growth factor binding proteins (IGFBPs) [72]. Three family members (IGFBP3, IGFBP4 and IGFBP5) were shown to be estrogenregulated in vitro with IGFBP3 and IGFBP5 being down-regulated by estrogen while IGFBP4 is upregulated [72].…”

“…Three family members (IGFBP3, IGFBP4 and IGFBP5) were shown to be estrogenregulated in vitro with IGFBP3 and IGFBP5 being down-regulated by estrogen while IGFBP4 is upregulated [72]. These effects were reversed by tamoxifen [72].…”

“…Three family members (IGFBP3, IGFBP4 and IGFBP5) were shown to be estrogenregulated in vitro with IGFBP3 and IGFBP5 being down-regulated by estrogen while IGFBP4 is upregulated [72]. These effects were reversed by tamoxifen [72]. In ovarian cancer samples obtained during the phase II trial, IGBP3 and IGFBP5 were lower, and IGFBP4 expression higher, in primary cancers that were responsive to letrozole relative to those that progressed on treatment, and this would be consistent with an estrogen-drive in responsive tumors as predicted by the in vitro experiment [72].…”