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-α (ERα)...

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Bibliographic Details
Published in:Cancer gene therapy 2022-11, Vol.29 (11), p.1697-1706
Main Authors: Roy, Stuti, Saha, Suryendu, Dhar, Debanil, Chakraborty, Puja, Singha Roy, Kumar, Mukherjee, Chitranjan, Gupta, Arnab, Bhattacharyya, Samir, Roy, Anup, Sengupta, Sanghamitra, Roychoudhury, Susanta, Nath, Somsubhra
Format: Article
Language:English
Subjects:
Adaptor Proteins, Signal Transducing - metabolism
Aneuploidy
Breast cancer
Breast Neoplasms - pathology
Estrogen Receptor alpha - genetics
Estrogen Receptor alpha - metabolism
Estrogen receptors
Female
Gene Expression Regulation, Neoplastic
Humans
Malignancy
Medical prognosis
Mitosis
Mitosis - genetics
Phosphorylation
Progesterone
Prospective Studies
Therapeutic targets
Tumors
Ubiquitination
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Summary: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-α (ERα) and progesterone receptor. Higher level of CUEDC2 in ERα+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 ERα 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 ERα+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.
ISSN:0929-1903
1476-5500
DOI:10.1038/s41417-022-00494-x