Time-Resolved Profiling Reveals ATF3 as a Novel Mediator of Endocrine Resistance in Breast Cancer

SIMPLE SUMMARY: Breast cancer is one of the leading causes of death for women worldwide. Patients whose tumors express estrogen receptor α (ERα) are the vast majority and are mostly treated with targeted endocrine therapy. However, resistance development poses an urgent clinical problem and the mechanisms of this phenomenon are not fully understood. In this study we identified ATF3 as a novel regulator of the response to therapy via rewiring of central signaling processes towards the adaptation to endocrine treatment. Our work adds a new piece to the complex puzzle of the molecular mechanisms at the basis of endocrine therapy resistance and proposes ATF3 and the downstream pathways as putative targets for novel combinatorial treatment strategies. ABSTRACT: Breast cancer is one of the leading causes of death for women worldwide. Patients whose tumors express Estrogen Receptor α account for around 70% of cases and are mostly treated with targeted endocrine therapy. However, depending on the degree of severity of the disease at diagnosis, 10 to 40% of these tumors eventually relapse due to resistance development. Even though recent novel approaches as the combination with CDK4/6 inhibitors increased the overall survival of relapsing patients, this remains relatively short and there is a urgent need to find alternative targetable pathways. In this study we profiled the early phases of the resistance development process to uncover drivers of this phenomenon. Time-resolved analysis revealed that ATF3, a member of the ATF/CREB family of transcription factors, acts as a novel regulator of the response to therapy via rewiring of central signaling processes towards the adaptation to endocrine treatment. ATF3 was found to be essential in controlling crucial processes such as proliferation, cell cycle, and apoptosis during the early response to treatment through the regulation of MAPK/AKT signaling pathways. Its essential role was confirmed in vivo in a mouse model, and elevated expression of ATF3 was verified in patient datasets, adding clinical relevance to our findings. This study proposes ATF3 as a novel mediator of endocrine resistance development in breast cancer and elucidates its role in the regulation of downstream pathways activities.