Figure 3

Schematic representation of the crosstalk between the IGF-1 system and estrogens in breast cancer. Binding of IGF-1 to IGF-1R triggers both PI3K/AKT/mTOR and MAPK/ERK signaling pathways, leading to enhanced breast cancer growth and proliferation. S6K1, a downstream molecule of the AKT/mTOR pathway induces phosphorylation of ERα. Activated ERα acts as transcription factor, through direct binding to promoter of target genes, consequently upregulating IGF-1, IGF-1R and other ERα-induced genes which also stimulate breast cancer progression. Prostaglandin E2 (PGE2) along with HER2 and both phosphorylated AKT and MAPK enhance aromatase activity through post-transcriptional mechanisms leading to elevated estrogen levels. Estrogens further contribute to transcriptional regulation of both IGF-1 and IGF-1R, consequently recycling the system’s signaling, enhancing growth and proliferation of breast tumors. S6K1: Ribosomal protein S6 kinase 1 protein; mTOR: mammalian target of rapamycin; HER2: human epidermal growth factor receptor 2 protein.