Epidermal Growth Factor Induces Insulin Receptor Substrate-2 in Breast Cancer Cells via c-Jun NH2-Terminal Kinase/Activator Protein-1 Signaling to Regulate Cell Migration

Abstract

The epidermal growth factor (EGF) and insulin-like growth factor (IGF) signaling pathways are critically involved in cancer development and progression. However, how these two signals cross-talk with each other to regulate cancer cell growth is not clearly understood. In this study, we found that EGF remarkably induced expression of major IGF signaling components, insulin receptor substrate (IRS)-1 and IRS-2, an effect that could be blocked by EGF receptor (EGFR) tyrosine kinase inhibitors. Although both extracellular signal-regulated kinase and c-Jun NH 2 -terminal kinase (JNK) signaling pathways were involved in the EGF up-regulation of IRS-1, the IRS-2 induction by EGF was specifically mediated by JNK signaling. Consistent with this, EGF increased IRS-2 promoter activity, which was associated with recruitment of activator protein-1 (AP-1) transcription factors and was inhibited by blocking AP-1 activity. Moreover, EGF treatment enhanced IGF-I and integrin engagement-elicited tyrosine phosphorylation of IRS and their downstream signaling, such as binding to phosphatidylinositol 3 ¶-kinase regulatory subunit p85. Finally, repressing the induction of IRS-2 levels abolished the EGF enhancement of cell motility, suggesting that increased IRS-2 is essential for the EGF regulation of breast cancer cell migration. Taken together, our results reveal a novel mechanism of cross-talk between the EGF and IGF signaling pathways, which could have implications in therapeutic applications of targeting EGFR in tumors. Because AP-1 activity is involved in breast cancer progression, our work may also suggest IRS-2 as a useful marker for aggressive breast cancer. (Cancer Res 2006; 66(10): 5304-13)

Insulin-like Growth Factor-1 Receptor and ErbB Kinase Inhibitor Combinations Block Proliferation and Induce Apoptosis through Cyclin D1 Reduction and Bax Activation

“…In addition, IGF-1 treatment of breast cancer and COS7 cells leads to EGFR phosphorylation (16,17). In other studies, amphiregulin activated IGF-1R phosphorylation in NSCLC cell lines (18), and epidermal growth factor treatment of the EGFR-positive breast cancer cell lines BT-20, MDA-MB-468, and T47D caused induction of IRS-1 and IRS-2 levels and resulted in potentiation of IGF-1-induced signaling in MDA-MB-468 cells (19). Increased IGF-1R signaling has also been implicated in resistance of NSCLC, breast cancer, and prostate cancer cells to the EGFR inhibitors, erlotinib and gefitinib (20,21), and of breast cancer cells to the anti-ErbB2 antibody, trastuzumab (22).…”

MLK3 Regulates Paxillin Phosphorylation in Chemokine-Mediated Breast Cancer Cell Migration and Invasion to Drive Metastasis

“…We previously showed MLK3-JNK signaling upregulates multiple AP-1-driven invasion genes and promotes a malignant phenotype in mammary epithelial cells (16). JNK is important in breast cancer cell migration and invasion and breast cancer progression (24,33,34). Yet, how MLK3-JNK signaling regulates cell migration machinery remains largely unknown.…”

MLK3 is critical for breast cancer cell migration and promotes a malignant phenotype in mammary epithelial cells

“…However, our findings that an MLK inhibitor can block the migration of invasive breast cancer cells and that JNK inhibition blocks MLK3-induced migration in MCF-7 and MCF10A cells supports the idea that, at least in the context of breast cancer, MLK3-JNK signaling is crucial for cell migration. Indeed, a significant body of literature indicates a requirement for JNK in cancer progression (Cui et al, 2006;Ching et al, 2007;Dhillon et al, 2007;Khatlani et al, 2007;Vivanco et al, 2007;Su et al, 2009;Wagner and Nebreda, 2009).…”