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

ABSTRACT: 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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE231544 | GEO | 2023/09/01

REPOSITORIES: GEO

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