Glucose-dependent insulin-like growth factor 1 secretion promotes breast cancer cell tumorigenesis

Background: IGF-1 is positively associated with breast cancer (BC) risk and recurrence; however, its role in relation to metabolic disorders, such as hyperglycemia, is not yet fully understood. Since N-glycosylation of the Ea peptide of IGF-1Ea pro-hormone influences the stability, secretion, and biological activity of mature IGF-1, this study explores the effect of glucose on IGF-1 involvement in BC cell proliferation, adopting a translational approach based on 3D co-culture models. Methods: To assess the biological effects of glucose-dependent IGF-1 secretion on BC cell growth, stable-transfected HEK-293 cells overexpressing the IGF-1Ea isoform were created (HEK-IGF1Ea). Under varying glucose concentrations, MCF7 and ZR-75-1 BC cells were directly and indirectly co-cultured with HEK-IGF1Ea cells and stimulated with HEK-IGF1Ea-conditioned media. Tumorigenic hallmarks were evaluated by spheroid formation analysis and activation of IGF-1 receptor (IGF-1R), ERK1/2, and Akt downstream proteins. Key findings: Across all the co-culture models, we found greater growth and spheroid formation of BC cells in the presence of glucose-induced IGF-1 produced in hyperglycemia-mimicking conditions. ZR-75-1 cells showed less significative spheroid formation due to a lower IGF-1R expression compared to MCF7 cells. Moreover, glucose-induced IGF-1 markedly increased ERK1/2 and Akt phosphorylation in MCF7 cells. Significance: This study reinforces the role of IGF-1 as a potential promoter of tumor progression, suggesting that IGF-1 may act as a molecular link between elevated glucose levels and tumor growth. In a tertiary prevention context, these results could translate into improving strategies based on lifestyle changes to control blood glucose and IGF-1 levels to prevent tumor recurrence.