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Forkhead box A1 (FOXA1) is a key mediator of insulin‐like growth factor I (IGF‐I) activity

The insulin‐like growth factor receptor (IGF‐IR) has been implicated in a number of human tumors, including breast cancer. Data from human breast tumors has demonstrated that IGF‐IR is over‐expressed and hyper‐phosphorylated. Additionally, microarray analysis has shown that IGF‐I treatment of MCF7 cells leads to a gene signature comprised of induced and repressed genes, which correlated with luminal B tumors. FOXA1, a forkhead family transcription factor, has been shown to be crucial for mammary ductal morphogenesis, similar to IGF‐IR, and expressed at high levels in luminal subtype B breast tumors. Here, we investigated the relationship between FOXA1 and IGF‐I action in breast cancer cells. We show that genes regulated by IGF‐I are enriched for FOXA1 binding sites, and knock down of FOXA1 blocked the ability of IGF‐I to regulate gene expression. IGF‐I treatment of MCF7 cells increased the half‐life of FOXA1 protein and this increase in half‐life appeared to be dependent on canonical IGF‐I signal transduction through both MAPK and AKT pathways. Finally, knock down of FOXA1 led to a decreased ability of IGF‐I to induce proliferation and protect against apoptosis. Together, these results demonstrate that IGF‐I can increase the stability of FOXA1 protein expression and place it as a critical mediator of IGF‐I regulation of gene expression and IGF‐I‐mediated biological responses. J. Cell. Biochem. 113: 110–121, 2012. © 2011 Wiley Periodicals, Inc.