FOXA1 phosphorylation by CDK4 prevents activation of novel chromatin regions and HER2 expression in breast cancer

Abstract The use of Cyclin Dependent Kinase 4/6 inhibitors (CDK4/6i) induce transcription in breast tumors. The control mechanism of such genomic changes and their physiological relevance are not elucidated yet. Now, we identified chromatin activation of tumors treated with CDK4/6i. These chromatin changes induce an increase of HER2 expression and signaling. Mechanically, we demonstrate that CDK4/6 binds to FOXA1 and phosphorylates its chromatin binding domain. The loss of FOXA1 phosphorylation allows the binding of this pioneer factor to novel chromatin regions enriched with genes involved in Receptor Tyrosine Kinase signaling. Our study demonstrates that FOXA1 is a new substrate of CDK4 and that its phosphorylation limits the binding of FOXA1 to conventional chromatin regions. Moreover, when patients are treated with CDK4/6i, a dephosphorylated FOXA1 binds to additional chromatin regions. By doing so, FOXA1 leads to an increase of HER2 expression and of the activation of HER2-MEK-ERK pathway in breast cancer patients.