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

Abstract

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-231cells 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.

Global analysis of L1-transcriptomes identified IGFBP-2 as a target of ezrin and NF-κB signaling that promotes colon cancer progression

“…As attempts of targeting cancer development by blocking IGFBP-2 activity [35][36][37] or ezrin phosphorylation 18 are already ongoing, we anticipate that further elucidation of the detailed molecular pathways by which L1 mediates human CRC metastasis will bring us closer to achieving this aim.…”

Role of Insulin-Like Growth Factor Binding Protein 2 in Lung Adenocarcinoma

“…9,11,36 Moreover, IGFBP-2 overexpression confers resistance to apoptosis induced by chemotherapy in breast cancer cells 6 and by androgen ablation in prostate cancer. 9 Serum IGFBP-2 can be used for prediction of chemotherapy response and prognosis in ovarian cancer 37 and acute lymphoblastic leukemia.…”

“…30,66 Further, our results suggested that IGFBP-2 is a therapeutic target in lung cancer, in line with the results in breast and ovarian cancers. 6,10 In general, lung adenocarcinomas typically showed a resistance to multiple cancer chemotherapy. Because cytoplasmic IGFBP-2 may provide cancer cells with an antiapoptotic ability, IGFBP-2 is an attractive therapeutic target especially for chemotherapy resistant tumors.…”

The Stromal Contribution to the Development of Resistance to New-Generation Drugs by Castration-Resistant Prostate Cancer

“…These steroids can feed back to the tumor cells, which, after ADT, have hypersensitive AR (8). Stromal steroidogenesis may play a significant part in the steroid milieu of the tumor microenvironment in addition to ADT driven upregulation of the steroidogenic potential of tumor cells, which are able to synthesize steroids from adrenal precursors, such as Dehydroepiandrosterone (DHEA), or de novo from precursors such as cholesterol or acetate through either the classical steroidogenesis pathway, or the backdoor pathway, which bypasses testosterone (T) as an intermediate for dihydrotestosterone (DHT) (3,(9)(10)(11).…”