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.

TOX3 is expressed in mammary ER+ epithelial cells and regulates ER target genes in luminal breast cancer

“…We also observed modest TOX3 upregulation in MCF-7 cells following IGF-1 treatment. This growth factor has been shown to contribute to breast cancer progression and endocrine resistance [ 29 , 41 ] through stabilization of FOXA1 protein in MCF-7 cells [ 42 ]. Moreover, FOXA1 alters the pattern of ER binding in ‘poor outcome/metastatic’ ER + breast cancer from that found in ER + ‘good outcome’ breast cancer [ 43 ].…”

Intrinsic breast cancer subtypes defined by estrogen receptor signalling—prognostic relevance of progesterone receptor loss

“…In the clinical setting, it may be best to clearly relate the HER2-positivity in these cases just to the therapeutic implications. However, as a number of other growth factor receptors, including EGFR, IGF1R, and IR may also be activated in luminal B breast carcinomas 38,39 resulting in increased proliferation, we tested a risk classification, in which loss of PR-expression (o10% positive nuclei/immunoreactive scoreo2) or high tumor proliferation (420% Ki-67-positive nuclei) were used to define luminal tumors as high risk. Although the cutoff-values for PR and Ki-67 were based on receiver operator characteristic-curve analysis with progression-free survival as stratifier, the same cutoffs for both PR and Ki-67 had also been used by previous studies to discriminate prognostically divergent groups of tumors.…”

Association of Genetic Polymorphisms in FOXA1 with the Progression of Genetic Susceptibility to Gastric Cancer

“…Functionally, FOXA1 is an important regulator of cell proliferation, cell cycle, and apoptosis. Both in vitro and in vivo studies have demonstrated that FOXA1 inhibition can inhibit the proliferation and induce apoptosis of gastric cancer cells [17][18][19]. Therefore, our data suggest that FOXA1 plays a carcinogenic role in gastric cancer by promoting cell proliferation and preventing apoptosis.…”