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

Abstract

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.

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Fig. 1: CUEDC2 degrades ERα in a mitosis dependent manner.
Fig. 2: Phosphorylated CUEDC2 degrades ERα.
Fig. 3: Effect of the CUEDC2-ERα inverse relationship on mitotic progression.
Fig. 4: Effect of the CUEDC2-ERα inverse relationship on the ploidy status of breast cancer cells.
Fig. 5: Analysis of CUEDC2 expression and its clinical relevance in primary breast malignancies.
Fig. 6: CUEDC2 regulates mitotic progression by regulating BUBR1 and MAD2 at transcription level.
Fig. 7: The CUEDC2-ERα crosstalk and clinical outcome in breast cancer.

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Acknowledgements

We acknowledge Dr. Gopal C. Kundu, NCCS, Pune, and Prof. Tanya Das, Bose Institute, Kolkata, for cell culture related support.

Funding

This study is supported by Early Career Award, Science & Engineering Research Board (SERB)-Dept. of Science and Technology (DST), Govt of India (File No. ECR/2015/000206) and, Grant-in-Aid, Department of Science & Technology and Biotechnology (DSTBT), Govt. of West Bengal (FST/P/S&T/9G-21/2016), awarded to SN. StR is supported by University Grants Commission- Junior Research Fellowship (UGC Ref. No.:771/ CSIR-UGC NET-2017). SR is the recipient of the ICMR Emeritus Scientist fellowship.

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StR, SS, SR and SN conceptualised the study. StR, SS, PC, KSR, CM performed the experiments. AG and SB provided the clinical samples and data. AR performed the histological evaluation. StR, SS, CM, SN analysed the data. StR and SN wrote the manuscript with input from all the authors.

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Correspondence to Somsubhra Nath.

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The authors declare no competing interests.

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The study was approved by the institutional ethics committee (IEC SGCCRI REF NO- 2016/3/4/SN/NON-REG/05/02) under regulation of the Indian Council of Medical Research (ICMR).

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Roy, S., Saha, S., Dhar, D. et al. Molecular crosstalk between CUEDC2 and ERα influences the clinical outcome by regulating mitosis in breast cancer. Cancer Gene Ther (2022). https://doi.org/10.1038/s41417-022-00494-x

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