Inhibition of Insulin-like Growth Factor–Binding Protein-3 Signaling through Sphingosine Kinase-1 Sensitizes Triple-Negative Breast Cancer Cells to EGF Receptor Blockade

Abstract

The type I EGF receptor (EGFR or ErbB1) and insulin-like growth factor-binding protein-3 (IGFBP-3) are highly expressed in triple-negative breast cancer (TNBC), a particularly aggressive disease that cannot be treated with conventional therapies targeting the estrogen or progesterone receptors (ER and PR), or HER2. We have shown previously in normal breast epithelial cells that IGFBP-3 potentiates growth-stimulatory signaling transduced by EGFR, and this is mediated by the sphingosine kinase-1 (SphK1)/sphingosine 1-phosphate (S1P) system. In this study, we investigated whether cotargeting the EGFR and SphK1/S1P pathways in TNBC cells results in greater growth inhibition compared with blocking either alone, and might therefore have novel therapeutic potential in TNBC. In four TNBC cell lines, exogenous IGFBP-3 enhanced ligand-stimulated EGFR activation, associated with increased SphK1 localization to the plasma membrane. The effect of exogenous IGFBP-3 on EGFR activation was blocked by pharmacologic inhibition or siRNA-mediated silencing of SphK1, and silencing of endogenous IGFBP-3 also suppressed EGF-stimulated EGFR activation. Real-time analysis of cell proliferation revealed a combined effect of EGFR inhibition by gefitinib and SphK1 inhibition using SKi-II. Growth of MDA-MB-468 xenograft tumors in mice was significantly inhibited by SKi-II and gefitinib when used in combination, but not as single agents. We conclude that IGFBP-3 promotes growth of TNBC cells by increasing EGFR signaling, that this is mediated by SphK1, and that combined inhibition of EGFR and SphK1 has potential as an anticancer therapy in TNBC in which EGFR and IGFBP-3 expression is high. Mol Cancer Ther; 13(2); 316-28. Ó2013 AACR.

Clinicopathological significance and impact on outcomes of the gene expression levels of IGF-1, IGF-2 and IGF-1R, IGFBP-3 in patients with colorectal cancer: Overexpression of the IGFBP-3 gene is an effective predictor of outcomes in patients with colorectal cancer

“…Additionally, Martin et al (39) demonstrated that IGFBP-3 enhanced EGF signaling and its proliferative effects via increased EGFR phosphorylation and the activation of MAP kinase signaling pathways in breast cancer cells in vitro. An associated previous study also reported that IGFBP-3 promotes the proliferation of breast cancer cells through increasing EGFR signaling mediated by SphK1 (40). Therefore, IGFBP-3 has been suggested to promote angiogenesis by inducing VEGF, thereby inducing EGFR signaling mediated by SphK1 and activation of MAP kinase signaling pathways.…”

Sphingosine-1-phosphate and estrogen signaling in breast cancer

“…We found that treatment mice bearing syngeneic breast tumors with the specific SphK1 inhibitor SK1-I not only suppressed S1P levels in the tumor and circulation, but importantly reduced tumor burden and metastases to lymph nodes and lungs (Nagahashi et al, 2012). Growth of MDA-MB-468 xenograft tumors in mice was significantly inhibited by the SphK1/2 inhibitor SKI-II and the tyrosine kinase inhibitor gefitinib when used in combination, but not as single agents (Martin et al, 2014). Although inhibition of SphK2 has also been reported to reduce tumorigenesis (Antoon et al, 2011b;Liu et al, 2013), further studies are needed to insure that these effects are solely dependent on inhibition of SphK2 activity.…”

Triple‑negative breast cancer and its?association with obesity (Review)

“…IGFBP-3 was positively correlated with BMI (51) and TNBC was found to be associated with high expression of epidermal growth factor receptor (EGFR) and IGFBP-3 (52,53). IGFBP-3 contributes to the growth of TNBC cells by increasing SphK1-mediated EGFR signaling (54).…”