Insulin-Like Growth Factor Binding Protein-2 Is a Novel Therapeutic Target Associated with Breast Cancer

• Published in: Clinical cancer research Vol. 14; no. 21; pp. 6944 - 6954
• Main Authors: SO, Alan I, LEVITT, Randy J, EIGL, Bernhard, FAZLI, Ladan, MURAMAKI, Motosugu, LEUNG, Sam, CHEANG, Maggie C. U, NIELSEN, Torsten O, GLEAVE, Martin, POLLAK, Michael
• Format: Journal Article
• Language: English
• Published: Philadelphia, PA American Association for Cancer Research 01.11.2008
• Subjects: Antineoplastic agents; antisense oligonucleotide; Biological and medical sciences; breast cancer; Breast Neoplasms - drug therapy; Cell Line, Tumor - metabolism; Cell Proliferation - drug effects; chemotherapy; Drug Delivery Systems; Gynecology. Andrology. Obstetrics; Humans; IGFBP-2; Insulin-Like Growth Factor Binding Protein 2 - metabolism; Insulin-Like Growth Factor Binding Protein 2 - physiology; Mammary gland diseases; MDA-MB-231; MDA-MB-468; Medical sciences; Oligodeoxyribonucleotides, Antisense - pharmacology; paclitaxel; Pharmacology. Drug treatments; Tissue Array Analysis; Tumors; Mammary gland diseases; Breast disease; Targeting; Targeted therapy; Breast cancer; Malignant tumor; Insulin-like growth factor binding protein 2; Cancer
• ISSN: 1078-0432; 1557-3265
• DOI: 10.1158/1078-0432.CCR-08-0408

Purpose: Insulin-like growth factor (IGF) binding proteins (IGFBP) modulate interactions of IGF ligands with the IGF-I receptor. The role of IGFBPs, and specifically IGFBP-2, in breast cancer progression has been poorly defined. This study assesses the effect of IGFBP-2 on the behavior of human breast cancer using clinical specimens as well as in vitro and in vivo experimental systems. Experimental Design: 4,181 primary invasive breast cancers and 120 benign breast tissue samples were identified for tumor tissue microarray construction and immunostained with IGFBP-2 antibody. Estrogen receptor-negative MDA-MB-231 cells constitutively overexpressing IGFBP-2 (MDA-MB-231BP-2) were created to assess the effect of IGFBP-2 gain-of-function. MDA-MB-468 cells, naturally expressing IGFBP-2, were used to determine the effect of IGFBP-2 loss-of-function using OGX-225, an antisense oligonucleotide drug candidate. Results: IGFBP-2 expression was significantly higher in breast cancer tissue compared with benign breast tissue. MDA-MB-231BP-2 cells grew more rapidly and were more resistant to paclitaxel both in vitro and in vivo compared with parental cells. OGX-225 decreased IGFBP-2 expression and attenuated the associated aggressive phenotype of MDA-MB-231BP-2 cells both in vitro and in vivo . Furthermore, OGX-225 inhibited the in vitro and in vivo growth of MDA-MB-468 cells. Conclusions: This study provides evidence that IGFBP-2 expression is associated with breast cancer. Novel therapeutics targeting IGFBP-2, such as OGX-225, merit further evaluation.