The IGF Pathway Regulates ERα through a S6K1-Dependent Mechanism in Breast Cancer Cells

The IGF pathway stimulates malignant behavior of breast cancer cells. Herein we identify the mammalian target of rapamycin (mTOR)/S6 kinase 1 (S6K1) axis as a critical component of IGF and estrogen receptor (ER)alpha cross talk. The insulin receptor substrate (IRS) adaptor molecules function downstream of IGF-I receptor and dictate a specific biological response, in which IRS-1 drives proliferation and IRS-2 is linked to motility. Although rapamycin-induced mTOR inhibition has been shown to block IGF-induced IRS degradation, we reveal differential effects on motility (up-regulation) and proliferation (down-regulation). Because a positive correlation between IRS-1 and ER alpha expression is thought to play a central role in the IGF growth response, we investigated the potential role of ER alpha as a downstream mTOR target. Small molecule inhibition and targeted knockdown of S6K1 blocked the IGF-induced ER alpha(S167) phosphorylation and did not influence ligand-dependent ER alpha(S118) phosphorylation. Inhibition of S6K1 kinase activity consequently ablated IGF-stimulated S6K1/ER alpha association, estrogen response element promoter binding and ER alpha target gene transcription. Moreover, site-specific ER alpha(S167) mutation reduced ER alpha target gene transcription and blocked IGF-induced colony formation. These findings support a novel link between the IGF pathway and ER alpha, in which the translation factor S6K1 affects transcription of ER alpha-regulated genes. (Molecular Endocrinology 25: 516-528, 2011)