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

Cyclin Dependent Kinase 4/6 inhibitors induce transcription in breast tumors via FOXA1 chromatin binding. 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, 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. Accordingly, we might envision a clinical benefit of adding antiHER2 therapy to delay development of resistance and therefore, to prolong PFS in patients yet receiving CDK4/6i. Three (3) ChIP-seq samples all derived from BT474 cell line: 1). wild type; 2) FOXA1_S234A mutation 3) FOXA1_S307A mutation. Two replicates each. 76bp long reads. Replicas were merged after mapping to the genome. Peaks were called using a) each of the mutants versus wild type BAMs (control) and wild type BAM vs each of the mutant BAMs (control) separately. Patient data: There were two samples taken from each of the patients from the same tumor: 1. sample at the week zero, no treatment/baseline; 2. sample at three weeks, after a 3 weeks treatment Letrozole+Ribociclib. Sample 1 was divided into: 1a: control/input; and 1b: ChIP-seq with anti-H3K4me2 antibody. Sample 2 was used just for the ChIP-seq with anti-H3K4me2 antibody. clinical_trial_name: CORALLEEN clinical_trial_id: NCT02513394 ***Please note that the raw FASTQ data files were submitted to ENA: PRJEB59327***