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.
authors.affiliation: State Key Laboratory of Proteomics, Institute of Basic Medical Sciences, China National Center of Biomedical Analysis, Beijing, China.
authors.forename: Xin
authors.initials: X
authors.lastname: Pan
authors.forename: Tao
authors.initials: T
authors.lastname: Zhou
authors.forename: Yan-Hong
authors.initials: YH
authors.lastname: Tai
authors.forename: Chenguang
authors.initials: C
authors.lastname: Wang
authors.forename: Jie
authors.initials: J
authors.lastname: Zhao
authors.forename: Yuan
authors.initials: Y
authors.lastname: Cao
authors.forename: Yuan
authors.initials: Y
authors.lastname: Chen
authors.forename: Pei-Jing
authors.initials: PJ
authors.lastname: Zhang
authors.forename: Ming
authors.initials: M
authors.lastname: Yu
authors.forename: Cheng
authors.initials: C
authors.lastname: Zhen
authors.forename: Rui
authors.initials: R
authors.lastname: Mu
authors.forename: Zhao-Fang
authors.initials: ZF
authors.lastname: Bai
authors.forename: Hui-Yan
authors.initials: HY
authors.lastname: Li
authors.forename: Ai-Ling
authors.initials: AL
authors.lastname: Li
authors.forename: Bing
authors.initials: B
authors.lastname: Liang
authors.forename: Zhao
authors.initials: Z
authors.lastname: Jian
authors.forename: Wei-Na
authors.initials: WN
authors.lastname: Zhang
authors.forename: Jiang-Hong
authors.initials: JH
authors.lastname: Man
authors.forename: Yan-Fei
authors.initials: YF
authors.lastname: Gao
authors.forename: Wei-Li
authors.initials: WL
authors.lastname: Gong
authors.forename: Li-Xin
authors.initials: LX
authors.lastname: Wei
authors.forename: Xue-Min
authors.initials: XM
authors.lastname: Zhang
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D018931:Antineoplastic Agents, Hormonal / Q000627:therapeutic use*; D001943:Breast Neoplasms / Q000188:drug therapy / Q000503:physiopathology*; D002352:Carrier Proteins / Q000096:biosynthesis / Q000502:physiology*; D045744:Cell Line, Tumor; D015536:Down-Regulation; D019008:Drug Resistance, Neoplasm / Q000502:physiology*; D047628:Estrogen Receptor alpha / Q000378:metabolism / Q000502:physiology; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000502:physiology; D006801:Humans; D051550:I-kappa B Kinase / Q000378:metabolism / Q000502:physiology; D008565:Membrane Proteins / Q000096:biosynthesis / Q000502:physiology*; D010766:Phosphorylation; D011980:Receptors, Progesterone / Q000378:metabolism / Q000502:physiology; D013629:Tamoxifen / Q000627:therapeutic use; D054875:Ubiquitination
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D018931:Antineoplastic Agents, Hormonal; C519556:CUEDC2 protein, human; D002352:Carrier Proteins; C506487:ESR1 protein, human; D047628:Estrogen Receptor alpha; D008565:Membrane Proteins; D011980:Receptors, Progesterone; D013629:Tamoxifen; C496559:CHUK protein, human; D051550:I-kappa B Kinase; C496560:IKBKB protein, human