Effects of FOXA1 phosphorylation on chromatin activation and HER2 expression in breast cancer

The use of Cyclin Dependent Kinase 4 inhibitors (CDK4i) in breast cancer patients induces transcriptional changes in tumors. In this work, we have identified early changes in chromatin activation of tumors treated with CDK4i. These chromatin changes induce an increase of HER2 expression in a significant number of patients treated with CDK4i. Mechanically, we demonstrate that the CDK4 binds to the pioneer factor FOXA1 and phosphorylates its chromatin binding domain. The loss of FOXA1 phosphorylation by chemical inhibition of CDK4 or by expressing FOXA1 phosphomutants in cells allows the binding of the FOXA1 to novel chromatin regions enriched with genes of the Receptor Tyrosine Kinase signaling. Additional functional experiments show an increase of HER2 expression and of signaling of HER2-MEK-ERK pathway upon CDK4 inhibition.