Skip to main content

Thank you for visiting You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

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) 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.

This is a preview of subscription content, access via your institution

Access options

Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.

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.


  1. Sung H, Ferlay J, Siegel RL, Laversanne M, Soerjomataram I, Jemal A, et al. Global Cancer Statistics 2020: GLOBOCAN Estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2021;71:209–49.

    Article  PubMed  Google Scholar 

  2. Pandit P, Patil R, Palwe V, Gandhe S, Patil R, Nagarkar R. Prevalence of molecular subtypes of breast cancer: A single institutional experience of 2062 patients. Eur J Breast Health. 2020;16:39–43.

    Article  PubMed  Google Scholar 

  3. Saha Roy S, Vadlamudi RK. Role of estrogen receptor signaling in breast cancer metastasis. Int J Breast Cancer. 2012;2012:654698.

    Article  PubMed  Google Scholar 

  4. Kumar N, Gulati HK, Sharma A, Heer S, Jassal AK, Arora L, et al. Most recent strategies targeting estrogen receptor alpha for the treatment of breast cancer. Mol Divers. 2021;25:603–24.

    Article  PubMed  Google Scholar 

  5. Belachew EB, Sewasew DT. Molecular mechanisms of endocrine resistance in estrogen-positive breast cancer. Front Endocrinol (Lausanne). 2021;12:599586.

    Article  Google Scholar 

  6. Pan X, Zhou T, Tai YH, Wang C, Zhao J, Cao Y, et al. Elevated expression of CUEDC2 protein confers endocrine resistance in breast cancer. Nat Med. 2011;17:708–14.

    Article  CAS  PubMed  Google Scholar 

  7. Shih SC, Prag G, Francis SA, Sutanto MA, Hurley JH, Hicke L. A ubiquitin-binding motif required for intramolecular monoubiquitylation, the CUE domain. EMBO J. 2003;22:1273–81.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Man J, Zhang X. CUEDC2: An emerging key player in inflammation and tumorigenesis. Protein Cell. 2011;2:699–703.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Gao YF, Li T, Chang Y, Wang YB, Zhang WN, Li WH, et al. Cdk1-phosphorylated CUEDC2 promotes spindle checkpoint inactivation and chromosomal instability. Nat Cell Biol. 2011;13:924–33.

    Article  CAS  PubMed  Google Scholar 

  10. Lin CY, Strom A, Vega VB, Kong SL, Yeo AL, Thomsen JS, et al. Discovery of estrogen receptor alpha target genes and response elements in breast tumor cells. Genome Biol. 2004;5:R66.

    Article  PubMed  PubMed Central  Google Scholar 

  11. Sabbah M, Courilleau D, Mester J, Redeuilh G. Estrogen induction of the cyclin D1 promoter: Involvement of a cAMP response-like element. Proc Natl Acad Sci USA. 1999;96:11217–22.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Wang C, Mayer JA, Mazumdar A, Fertuck K, Kim H, Brown M, et al. Estrogen induces c-myc gene expression via an upstream enhancer activated by the estrogen receptor and the AP-1 transcription factor. Mol Endocrinol. 2011;25:1527–38.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. JavanMoghadam S, Weihua Z, Hunt KK, Keyomarsi K. Estrogen receptor alpha is cell cycle-regulated and regulates the cell cycle in a ligand-dependent fashion. Cell Cycle. 2016;15:1579–90.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Matson DR, Stukenberg PT. Spindle poisons and cell fate: a tale of two pathways. Mol Inter. 2011;11:141–50.

    Article  CAS  Google Scholar 

  15. Elmaci I, Altinoz MA, Sari R, Bolukbasi FH. Phosphorylated Histone H3 (PHH3) as a novel cell proliferation marker and prognosticator for meningeal tumors: A short review. Appl Immunohistochem Mol Morphol. 2018;26:627–31.

    Article  CAS  PubMed  Google Scholar 

  16. Watson ER, Brown NG, Peters JM, Stark H, Schulman BA. Posing the APC/C E3 Ubiquitin Ligase to Orchestrate Cell Division. Trends Cell Biol. 2019;29:117–34.

    Article  CAS  PubMed  Google Scholar 

  17. Musacchio A, Salmon ED. The spindle-assembly checkpoint in space and time. Nat Rev Mol Cell Biol. 2007;8:379–93.

    Article  CAS  PubMed  Google Scholar 

  18. Zhou Z, He M, Shah AA, Wan Y. Insights into APC/C: From cellular function to diseases and therapeutics. Cell Div. 2016;11:9.

    Article  PubMed  PubMed Central  Google Scholar 

  19. Encarnacion CA, Ciocca DR, McGuire WL, Clark GM, Fuqua SA, Osborne CK. Measurement of steroid hormone receptors in breast cancer patients on tamoxifen. Breast Cancer Res Treat. 1993;26:237–46.

    Article  CAS  PubMed  Google Scholar 

  20. Shi L, Dong B, Li Z, Lu Y, Ouyang T, Li J, et al. Expression of ER-{alpha}36, a novel variant of estrogen receptor {alpha}, and resistance to tamoxifen treatment in breast cancer. J Clin Oncol. 2009;27:3423–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Musgrove EA, Sutherland RL. Biological determinants of endocrine resistance in breast cancer. Nat Rev Cancer. 2009;9:631–43.

    Article  CAS  PubMed  Google Scholar 

  22. Masoud V, Pages G. Targeted therapies in breast cancer: New challenges to fight against resistance. World J Clin Oncol. 2017;8:120–34.

    Article  PubMed  PubMed Central  Google Scholar 

  23. Rani A, Stebbing J, Giamas G, Murphy J. Endocrine resistance in hormone receptor positive breast cancer-from mechanism to therapy. Front Endocrinol (Lausanne). 2019;10:245.

    Article  Google Scholar 

  24. De Amicis F, Thirugnansampanthan J, Cui Y, Selever J, Beyer A, Parra I, et al. Androgen receptor overexpression induces tamoxifen resistance in human breast cancer cells. Breast Cancer Res Treat. 2010;121:1–11.

    Article  CAS  PubMed  Google Scholar 

  25. Lord CJ, Ashworth A. BRCAness revisited. Nat Rev Cancer. 2016;16:110–20.

    Article  CAS  PubMed  Google Scholar 

  26. Vagia E, Mahalingam D, Cristofanilli M. The landscape of targeted therapies in TNBC. Cancers (Basel). 2020;12:916.

    Article  Google Scholar 

  27. Zhou Q, Atadja P, Davidson NE. Histone deacetylase inhibitor LBH589 reactivates silenced estrogen receptor alpha (ER) gene expression without loss of DNA hypermethylation. Cancer Biol Ther. 2007;6:64–9.

    Article  CAS  PubMed  Google Scholar 

  28. Brinkman JA, El-Ashry D. ER re-expression and re-sensitization to endocrine therapies in ER-negative breast cancers. J Mammary Gland Biol Neoplasia. 2009;14:67–78.

    Article  PubMed  Google Scholar 

  29. Saxena NK, Sharma D. Epigenetic reactivation of estrogen receptor: Promising tools for restoring response to endocrine therapy. Mol Cell Pharm. 2010;2:191–202.

    CAS  Google Scholar 

  30. Vesuna F, Lisok A, Kimble B, Domek J, Kato Y, van der Groep P, et al. Twist contributes to hormone resistance in breast cancer by downregulating estrogen receptor-alpha. Oncogene 2012;31:3223–34.

    Article  CAS  PubMed  Google Scholar 

  31. Sarkar S, Ghosh A, Banerjee S, Maity G, Das A, Larson MA, et al. CCN5/WISP-2 restores ER- proportional, variant in normal and neoplastic breast cells and sensitizes triple negative breast cancer cells to tamoxifen. Oncogenesis 2017;6:e340.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Bayliss J, Hilger A, Vishnu P, Diehl K, El-Ashry D. Reversal of the estrogen receptor negative phenotype in breast cancer and restoration of antiestrogen response. Clin Cancer Res. 2007;13:7029–36.

    Article  CAS  PubMed  Google Scholar 

  33. Zhang PJ, Zhao J, Li HY, Man JH, He K, Zhou T, et al. CUE domain containing 2 regulates degradation of progesterone receptor by ubiquitin-proteasome. EMBO J. 2007;26:1831–42.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Vasudevan A, Schukken KM, Sausville EL, Girish V, Adebambo OA, Sheltzer JM. Aneuploidy as a promoter and suppressor of malignant growth. Nat Rev Cancer. 2021;21:89–103.

    Article  CAS  PubMed  Google Scholar 

  35. Ben-David U, Amon A. Context is everything: Aneuploidy in cancer. Nat Rev Genet. 2020;21:44–62.

    Article  CAS  PubMed  Google Scholar 

  36. Carroll JS. Mechanisms of oestrogen receptor (ER) gene regulation in breast cancer. Eur J Endocrinol. 2016;175:R41–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Cho JH, Yoon MS, Koo JB, Kim YS, Lee KS, Lee JH, et al. The progesterone receptor as a transcription factor regulates phospholipase D1 expression through independent activation of protein kinase A and Ras during 8-Br-cAMP-induced decidualization in human endometrial stromal cells. Biochem J. 2011;436:181–91.

    Article  CAS  PubMed  Google Scholar 

Download references


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


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.

Author information

Authors and Affiliations



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.

Corresponding author

Correspondence to Somsubhra Nath.

Ethics declarations

Conflict of interest

The authors declare no competing interests.

Ethics approval and consent to participate

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).

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

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 29, 1697–1706 (2022).

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI:


Quick links