Molecular crosstalk between CUEDC2 and ERα influences the clinical outcome by regulating mitosis in breast cancer

Development of endocrine resistance in hormone-receptor-positive (HR+ve) subtype and lack of definitive target in triple-negative subtype challenge breast cancer management. Contributing to such endocrine resistance is a protein called CUEDC2. It degrades hormone receptors, estrogen receptor-alpha (ER alpha) and progesterone receptor. Higher level of CUEDC2 in ER alpha+ve breast cancer corresponded to poorer disease prognosis. It additionally influences mitotic progression. However, the crosstalk of these two CUEDC2-driven functions in the outcome of breast cancer remained elusive. We showed that CUEDC2 degrades ER alpha during mitosis, utilising the mitotic-ubiquitination-machinery. We elucidated the importance of mitosis-specific phosphorylation of CUEDC2 in this process. Furthermore, upregulated CUEDC2 overrode mitotic arrest, increasing aneuploidy. Finally, recruiting a prospective cohort of breast cancer, we found significantly upregulated CUEDC2 in HR-ve cases. Moreover, individuals with higher CUEDC2 levels showed a poorer progression-free-survival. Together, our data confirmed that CUEDC2 up-regulation renders ER alpha+ve malignancies to behave essentially as HR-ve tumors with the prevalence of aneuploidy. This study finds CUEDC2 as a potential prognostic marker and a therapeutic target in the clinical management of breast cancer.

Automated summary

This study reveals the role of CUEDC2 in breast cancer, especially in endocrine resistance and mitotic progression. Upregulation of CUEDC2 renders ERα+ve tumors behave similarly to HR-ve tumors with an increase in aneuploidy. Furthermore, CUEDC2 is identified as a potential prognostic marker and therapeutic target in breast cancer management.