Elevated expression of CUEDC2 protein confers endocrine resistance in breast cancer

Xin Pan; Tao Zhou; Yan Hong Tai; Chenguang Wang; Jie Zhao; Yuan Cao; Yuan Chen; Pei Jing Zhang; Ming Yu; Cheng Zhen; Rui Mu; Zhao Fang Bai; Hui Yan Li; Ai Ling Li; Bing Liang; Zhao Jian; Wei Na Zhang; Jiang Hong Man; Yan Fei Gao; Wei Li Gong; Li Xin Wei; Xue Min Zhang

doi:10.1038/nm.2369

Elevated expression of CUEDC2 protein confers endocrine resistance in breast cancer

Xin Pan, Tao Zhou, Yan Hong Tai, Chenguang Wang, Jie Zhao, Yuan Cao, Yuan Chen, Pei Jing Zhang, Ming Yu, Cheng Zhen, Rui Mu, Zhao Fang Bai, Hui Yan Li, Ai Ling Li, Bing Liang, Zhao Jian, Wei Na Zhang, Jiang Hong Man, Yan Fei Gao, Wei Li GongLi Xin Wei, Xue Min Zhang

Experimental Radiation Oncology

Research output: Contribution to journal › Article › peer-review

116 Scopus citations

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.

Original language	English (US)
Pages (from-to)	708-714
Number of pages	7
Journal	Nature medicine
Volume	17
Issue number	6
DOIs	https://doi.org/10.1038/nm.2369
State	Published - Jun 2011

ASJC Scopus subject areas

General Biochemistry, Genetics and Molecular Biology

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10.1038/nm.2369

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Pan, X., Zhou, T., Tai, Y. H., Wang, C., Zhao, J., Cao, Y., Chen, Y., Zhang, P. J., Yu, M., Zhen, C., Mu, R., Bai, Z. F., Li, H. Y., Li, A. L., Liang, B., Jian, Z., Zhang, W. N., Man, J. H., Gao, Y. F., ... Zhang, X. M. (2011). Elevated expression of CUEDC2 protein confers endocrine resistance in breast cancer. Nature medicine, 17(6), 708-714. https://doi.org/10.1038/nm.2369

@article{4ac6ff9f299d4a7789ae0d6d2162c15d,

title = "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.",

author = "Xin Pan and Tao Zhou and Tai, {Yan Hong} and Chenguang Wang and Jie Zhao and Yuan Cao and Yuan Chen and Zhang, {Pei Jing} and Ming Yu and Cheng Zhen and Rui Mu and Bai, {Zhao Fang} and Li, {Hui Yan} and Li, {Ai Ling} and Bing Liang and Zhao Jian and Zhang, {Wei Na} and Man, {Jiang Hong} and Gao, {Yan Fei} and Gong, {Wei Li} and Wei, {Li Xin} and Zhang, {Xue Min}",

note = "Funding Information: 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.).",

year = "2011",

month = jun,

doi = "10.1038/nm.2369",

language = "English (US)",

volume = "17",

pages = "708--714",

journal = "Nature medicine",

issn = "1078-8956",

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T1 - Elevated expression of CUEDC2 protein confers endocrine resistance in breast cancer

AU - Pan, Xin

AU - Zhou, Tao

AU - Tai, Yan Hong

AU - Wang, Chenguang

AU - Zhao, Jie

AU - Cao, Yuan

AU - Chen, Yuan

AU - Zhang, Pei Jing

AU - Yu, Ming

AU - Zhen, Cheng

AU - Mu, Rui

AU - Bai, Zhao Fang

AU - Li, Hui Yan

AU - Li, Ai Ling

AU - Liang, Bing

AU - Jian, Zhao

AU - Zhang, Wei Na

AU - Man, Jiang Hong

AU - Gao, Yan Fei

AU - Gong, Wei Li

AU - Wei, Li Xin

AU - Zhang, Xue Min

N1 - Funding Information: 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.).

PY - 2011/6

Y1 - 2011/6

N2 - 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.

AB - 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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JO - Nature medicine

JF - Nature medicine

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ER -

Elevated expression of CUEDC2 protein confers endocrine resistance in breast cancer

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