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Elevated expression of CUEDC2 protein confers endocrine resistance in breast cancer

Abstract

Endocrine resistance is a major obstacle to hormonal therapy for breast cancers. Although reduced expression of estrogen receptor-α (ER-α) is a known contributing factor to endocrine resistance, the mechanism of ER-α downregulation in endocrine resistance is still not fully understood. Here we report that CUE domain–containing protein-2 (CUEDC2), a ubiquitin-binding motif–containing protein, is a key factor in endocrine resistance in breast cancer. We show that CUEDC2 modulates ER-α protein stability through the ubiquitin-proteasome pathway. Through the study of specimens from a large cohort of subjects with breast cancer, we found a strong inverse correlation between CUEDC2 and ER-α protein expression. Notably, subjects with tumors that highly expressed CUEDC2 had poor responsiveness to tamoxifen treatment and high potential for relapse. We further show that ectopic CUEDC2 expression impaired the responsiveness of breast cancer cells to tamoxifen. Therefore, our findings suggest that CUEDC2 is a crucial determinant of resistance to endocrine therapies in breast cancer.

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Figure 1: CUEDC2 downregulates ER-α stability through the ubiquitin-proteasome pathway.
Figure 2: CUEDC2 interacts with ER-α and promotes ER-α ubiquitination and degradation.
Figure 3: CUEDC2 expression is elevated in breast cancer tumors.
Figure 4: Inverse correlation between CUEDC2 and ER-α expression in breast cancers.
Figure 5: CUEDC2 predicts clinical outcome of breast cancer with tamoxifen therapy.
Figure 6: Overexpression of CUEDC2 decreases sensitivity of breast cancer cells to tamoxifen.

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Acknowledgements

We thank Z. Liu for critical reading of the manuscript, L. Hu for assistance with statistical analysis and Q. Ye at Beijing Institute of Biotechnology for DBD-ER-α plasmids. This work was supported by grants from the China National Natural Science Foundation (No. 91029733, No. 30830097 and No. 30900754), the China National High Technology Research and Development Program (Grant 2009AA02Z103), the China National Basic Research Program (Grant 2010CB911900, 2010CB529404), the Key State Science and Technology Projects (2009ZX09503-001, 2009ZX09501-031, 2009ZX09301-002 and 2008ZX10002-016). Work conducted at Thomas Jefferson University is funded in part by a Pennsylvania Department of Health grant (to C.W.).

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Authors

Contributions

X.-M.Z., T.Z. and C.W. supervised the project. X.P., T.Z. and J.Z. designed and conducted the experiments, including immunoprecipitation, RT-PCR, western blotting and drug sensitivity studies. Y.-H.T., under the supervision of L.-X.W., obtained clinical samples and did immunohistochemistry analysis. Y. Cao constructed the CRD. M.Y. and R.M. prepared CUEDC2-specific antibody. B.L., Z.-F.B. and J.-H.M. constructed stable cell lines. X.P., C.Z., Z.J. and W.-L.G. carried out animal experiments. Y. Chen, Y.-F.G., P.-J.Z. and W.-N.Z. contributed to the preparation of cDNA vector constructs. X.P., T.Z., C.W., X.-M.Z and H.-Y.L. analyzed the data. X.P. and Y.-H.T. did the statistical analyses. X.-M.Z., X.P., T.Z. and A.-L.L. wrote the manuscript.

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Correspondence to Li-Xin Wei or Xue-Min Zhang.

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Pan, X., Zhou, T., Tai, YH. et al. Elevated expression of CUEDC2 protein confers endocrine resistance in breast cancer. Nat Med 17, 708–714 (2011). https://doi.org/10.1038/nm.2369

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