Distinct activities OF IGF1R and INSR on ERK and AKT signaling pathways in breast cancer cells

Introduction: Breast cancer development and progression are influenced by insulin-like growth factor-1 (IGF1R) and insulin (INSR) receptor signaling, which drive typical cancer phenotypes such as cell growth, proliferation, and migration. However, it is still unknown why IGF1R and INSR, despite the fact that they share most of their downstream cytoplasmic signaling mediators, exhibit, for the most part, distinct, well-defined functions.

Aim: To evaluate the specific impact of IGF1R and INSR on ERK and AKT pathways in breast cancer-derived cell lines.

Methods: MCF7-derived stable cell lines lacking IGF1R or INSR expression (IGF1R-KD, INSR-KD) were employed in the current research. The expression and activation of specific downstream genes involved in IGF1 and insulin signaling was assessed by Western blots. IGF1R promoter activity was measured by luciferase assays. Proliferation was evaluated by XTT assays.

Results: Western blotting analyses showed that IGF1R silencing had a major impact on nuclear ERK1/2 and AKT activation. Promoter measurements indicate that ERK2 and AKT stimulated IGF1R promoter activity, although this effect was markedly reduced in IGF1R-KD and INSR-KD cells.

Conclusions: Our results indicate that insulin and IGF1 pathways have different effects on the subcellular distribution (and, particularly, the nuclear presence) of ERK1/2 and AKT molecules. Both cytoplasmic mediators are capable of binding and transactivating the IGF1R promoter. Our data is consistent with the notion that, in addition to their classical role as targets for insulin-like molecules, both ERK1/2 and AKT are involved in transcriptional control of the IGF1R gene.