title: Forkhead box A1 (FOXA1) is a key mediator of insulin-like growth factor I (IGF-I) activity.
abstract: 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.
authors: Lester and Sue Smith Breast Center, Baylor College of Medicine, Houston, Texas 77030, USA.
authors: Adam S
authors: AS
authors: Potter
authors: Angelo J
authors: AJ
authors: Casa
authors: Adrian V
authors: AV
authors: Lee
mesh_terms: D017209:Apoptosis; D001665:Binding Sites; D001943:Breast Neoplasms / Q000378:metabolism*; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D005260:Female; D005786:Gene Expression Regulation / Q000235:genetics; D051541:Hepatocyte Nuclear Factor 3-alpha / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000235:genetics / Q000378:metabolism*; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D058539:Phosphatidylinositol 3-Kinase / Q000378:metabolism; D034622:RNA Interference; D034741:RNA, Small Interfering; D015398:Signal Transduction
chemical_list: C496499:FOXA1 protein, human; D051541:Hepatocyte Nuclear Factor 3-alpha; D034741:RNA, Small Interfering; D007334:Insulin-Like Growth Factor I; D058539:Phosphatidylinositol 3-Kinase; D020928:Mitogen-Activated Protein Kinases