Elevated expression of CUEDC2 protein confers endocrine resistance in breast cancer

• Published in: Nature medicine Vol. 17; no. 6; pp. 708 - 714
• Main Authors: Pan, Xin, Zhou, Tao, Tai, Yan-Hong, Wang, Chenguang, Zhao, Jie, Cao, Yuan, Chen, Yuan, Zhang, Pei-Jing, Yu, Ming, Zhen, Cheng, Mu, Rui, Bai, Zhao-Fang, Li, Hui-Yan, Li, Ai-Ling, Liang, Bing, Jian, Zhao, Zhang, Wei-Na, Man, Jiang-Hong, Gao, Yan-Fei, Gong, Wei-Li, Wei, Li-Xin, Zhang, Xue-Min
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01.06.2011; Nature Publishing Group
• Subjects: 631/67/1059/2326; 692/53/2423; 692/699/67/1347; 692/700/565/1331/238; Antineoplastic Agents, Hormonal - therapeutic use; Biomedical and Life Sciences; Biomedicine; Breast cancer; Breast Neoplasms - drug therapy; Breast Neoplasms - physiopathology; Cancer Research; Care and treatment; Carrier Proteins - biosynthesis; Carrier Proteins - physiology; Cell Line, Tumor; Down-Regulation; Drug Resistance, Neoplasm - physiology; Endocrine therapy; Estrogen Receptor alpha - metabolism; Estrogen Receptor alpha - physiology; Estrogens; Female; Gene expression; Gene Expression Regulation, Neoplastic - physiology; Genetic aspects; Health aspects; Hormone therapy; Humans; I-kappa B Kinase - metabolism; I-kappa B Kinase - physiology; Infectious Diseases; Membrane Proteins - biosynthesis; Membrane Proteins - physiology; Metabolic Diseases; Molecular Medicine; Neurosciences; Phosphorylation; Proteins; Receptors, Progesterone - metabolism; Receptors, Progesterone - physiology; Signal transduction; Tamoxifen - therapeutic use; Ubiquitination; United States; China
• ISSN: 1078-8956; 1546-170X; 1546-170X
• DOI: 10.1038/nm.2369

Downregulation of estrogen receptor-α (ER-α) in breast tumors can mediate resistance to ER-α–targeted therapies such as tamoxifen. This report sheds light on a therapy resistance–conferring adaptation by identifying a new regulator of ER-α stability. CUE domain–containing protein-2 (CUEDC2) can bind to and promote degradation of ER-α, thereby driving tamoxifen resistance. Elevated CUEDC2 elevation in human breast cancers correlates with attenuated prognosis after tamoxifen treatment, thus suggesting its potential as a clinical predictor. 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.