Targeting Insulin-Like Growth Factor Binding Protein-3 Signaling in Triple-Negative Breast Cancer

Abstract

Insulin-like growth factor binding protein-3 (IGFBP-3) is a key regulatory molecule of the IGF axis and can function in a tissue-specific way as both a tumor suppressor and promoter. Triple-negative breast cancer (TNBC) has high tumor expression of IGFBP-3 associated with markers of poor prognosis and, although accounting for 15–20% of all breast cancers, is responsible for disproportionate rates of morbidity and mortality. Because they lack estrogen and progesterone receptors and overexpression of HER2, TNBC are resistant to treatments that target these molecules, making the development of new therapies an important goal. In addition to frequent high expression of IGFBP-3, these tumors also express EGFR highly, but targeting EGFR signaling alone in TNBC has been of little success. Identification of a functional growth-stimulatory interaction between EGFR and IGFBP-3 signaling prompted investigation into cotargeting these pathways as a novel therapy for TNBC. This involves inhibition of both EGFR kinase activity and a mediator of IGFBP-3's stimulatory bioactivity, sphingosine kinase-1 (SphK1), and has shown promise in a preclinical setting. Functional interaction between EGFR and IGFBP-3 may also promote chemoresistance in TNBC, and delineating the mechanisms involved may identify additional targets for development of therapies in cancers that express both IGFBP-3 and EGFR.

IGFBP-3 Blocks Hyaluronan-CD44 Signaling, Leading to Increased Acetylcholinesterase Levels in A549 Cell Media and Apoptosis in a p53-Dependent Manner

“…IGFBP-3 is also known to regulate cell survival independently of the IGF/IGF-IR axis [39][40][41][42] . Expression of IGFBP-3 is reduced 43 in lung cancer and associated with poor diagnosis in patients with stage I NSCLC [44][45][46][47][48] . There is an inverse relationship between plasma or serum levels of the protein and lung cancer risk 34,39,49 .…”

Suppression of tumor growth via IGFBP3 depletion as a potential treatment in glioma

“…1 It was first identified as a binding partner of IGFs for stabilizing the IGFs in blood and an inhibitor of IGF-1 receptor (IGF1R) signaling by blocking IGF binding to receptors in tissues. 2 Overexpression of IGFBP3 is found in renal clear cell carcinomas, 23 head and neck squamous cancers, 15 pancreatic ductal adenocarcinomas, 29 and aggressive breast cancers, 17 and its expression is associated with poor patient outcome. IGFBP3 functions as a tumor promoter by enhancing cell growth through increasing sphingosine kinase-1 (SphK1) expression and sphingosine-1 phosphate (S1P) formation, which transactivates epidermal growth factor receptor (EGFR) or IGF1R signaling pathways.…”

Novel Candidate Biomarkers of Chemoradiosensitivity in Esophageal Squamous Cell Carcinoma: A Systematic Review

“…Insulin-like growth factor binding protein-3 (IGFBP-3) is a key regulatory molecule in the IGF axis and functions in a tissue-specific way as both a tumor suppressor and promoter [11]. Zhao et al [12] reported that ESCC patients carrying the IGFBP-3 rs2854744 GG or GC genotype have a significantly better response to CRT and longer OS than those with the CC genotype.…”