ZEB1 induces ER-α promoter hypermethylation and confers antiestrogen resistance in breast cancer

被引:81
|
作者
Zhang, Jianbo [1 ]
Zhou, Chen [2 ,3 ]
Jiang, Huimin [2 ,3 ]
Liang, Lin [2 ,3 ]
Shi, Wen [2 ,3 ]
Zhang, Quansheng [4 ]
Sun, Peiqing [5 ]
Xiang, Rong [2 ,3 ]
Wang, Yue [2 ]
Yang, Shuang [2 ,3 ]
机构
[1] Chongqing Med Univ, Dept Gastrointestinal Surg, Affiliated Hosp 2, Chongqing 400010, Peoples R China
[2] Nankai Univ, Dept Med Genet, Tianjin Key Lab Tumor Microenvironm & Neurovasc R, Med Coll, 94 Weijin Rd, Tianjin 300071, Peoples R China
[3] Nankai Univ, Project Collaborat Innovat Ctr Biotherapy 2011, Minist Educ, Med Coll, Tianjin 300071, Peoples R China
[4] Tianjin First Ctr Hosp, Tianjin Key Lab Organ Transplantat, Tianjin 300192, Peoples R China
[5] Wake Forest Univ, Dept Canc Biol, Sch Med, Winston Salem, NC 27157 USA
来源
CELL DEATH & DISEASE | 2017年 / 8卷
基金
中国国家自然科学基金;
关键词
EPITHELIAL-MESENCHYMAL TRANSITION; ESTROGEN-RECEPTOR-ALPHA; E-CADHERIN EXPRESSION; TRANSCRIPTIONAL REPRESSOR; PROGESTERONE-RECEPTORS; ENDOCRINE RESISTANCE; GENE-EXPRESSION; BETA-CATENIN; MECHANISMS; PLASTICITY;
D O I
10.1038/cddis.2017.154
中图分类号
Q2 [细胞生物学];
学科分类号
071009 ; 090102 ;
摘要
Antiestrogen resistance is a major obstacle to endocrine therapy for breast cancers. Although reduced estrogen receptor-alpha (ER-alpha) expression is a known contributing factor to antiestrogen resistance, the mechanisms of ER-alpha downregulation in antiestrogen resistance are not fully understood. Here, we report that ectopic zinc-finger E-box binding homeobox 1 (ZEB1) is associated with ER-alpha deficiency in breast cancer cells and thus confers antiestrogen resistance. Mechanistically, ZEB1 represses ER-alpha transcription by forming a ZEB1/DNA methyltransferase (DNMT) 3B/histone deacetylase (HDAC) 1 complex on the ER-alpha promoter, leading to DNA hypermethylation and the silencing of ER-alpha. Thus, ectopic ZEB1 downregulates ER-alpha expression and subsequently attenuates cell growth inhibition by antiestrogens, such as tamoxifen and fulvestrant. Notably, the depletion of ZEB1 by RNA interference causes ER-alpha promoter demethylation, restores ER-alpha expression, and increases the responsiveness of breast cancer cells to antiestrogen treatment. By studying specimens from a large cohort of subjects with breast cancer, we found a strong inverse correlation between ZEB1 and ER-alpha protein expression. Moreover, breast tumors that highly express ZEB1 exhibit ER-alpha promoter hypermethylation. Using a nude mouse xenograft model, we further confirmed that the downregulation of ZEB1 expression restores the responsiveness of breast cancer cells to antiestrogen therapy in vivo. Therefore, our findings suggest that ZEB1 is a crucial determinant of resistance to antiestrogen therapies in breast cancer.
引用
收藏
页码:e2732 / e2732
页数:11
相关论文
共 50 条
  • [21] ERβ1 inhibits metastasis of androgen receptor-positive triple-negative breast cancer by suppressing ZEB1
    Song, Wei
    Tang, Lin
    Xu, Yumei
    Sun, Qian
    Yang, Fang
    Guan, Xiaoxiang
    JOURNAL OF EXPERIMENTAL & CLINICAL CANCER RESEARCH, 2017, 36
  • [22] Expression of glucose transporter GLUT-1 and estrogen receptors ER-α and ER-β in human breast cancer
    Laudanski, P
    Koda, M
    Kozlowski, L
    Swiatecka, J
    Wojtukiewicz, M
    Sulkowski, S
    Wolczynski, S
    NEOPLASMA, 2004, 51 (03) : 164 - 168
  • [23] Cooperative interaction between ERα and the EMT-inducer ZEB1 reprograms breast cancer cells for bone metastasis
    Nastaran Mohammadi Ghahhari
    Magdalena K. Sznurkowska
    Nicolas Hulo
    Lilia Bernasconi
    Nicola Aceto
    Didier Picard
    Nature Communications, 13
  • [24] Cooperative interaction between ERα and the EMT-inducer ZEB1 reprograms breast cancer cells for bone metastasis
    Ghahhari, Nastaran Mohammadi
    Sznurkowska, Magdalena K.
    Hulo, Nicolas
    Bernasconi, Lilia
    Aceto, Nicola
    Picard, Didier
    NATURE COMMUNICATIONS, 2022, 13 (01)
  • [25] Autophagy and senescence facilitate the development of antiestrogen resistance in ER positive breast cancer
    Mcgrath, Michael K.
    Abolhassani, Ali
    Guy, Luke
    Elshazly, Ahmed M.
    Barrett, John T.
    Mivechi, Nahid F.
    Gewirtz, David A.
    Schoenlein, Patricia V.
    FRONTIERS IN ENDOCRINOLOGY, 2024, 15
  • [26] Autophagy facilitates the progression of ERα-positive breast cancer cells to antiestrogen resistance
    Schoenlein, Patricia V.
    Periyasamy-Thandavan, Sudharsan
    Samaddar, Julia S.
    Jackson, William H.
    Barrett, John T.
    AUTOPHAGY, 2009, 5 (03) : 400 - 403
  • [27] RETRACTED: Inhibition of ZEB1-AS1 confers cisplatin sensitivity in breast cancer by promoting microRNA-129-5p-dependent ZEB1 downregulation (Retracted Article)
    Gao, Jin
    Yuan, Yuan
    Zhang, Lili
    Yu, Shaorong
    Lu, Jianwei
    Feng, Jifeng
    Hu, Sainan
    CANCER CELL INTERNATIONAL, 2020, 20 (01)
  • [28] Opposite Roles for ZEB1 and TMEJ in the Regulation of Breast Cancer Genome Stability
    Prodhomme, Melanie K.
    Pericart, Sarah
    Pommier, Roxane M.
    Morel, Anne-Pierre
    Brunac, Anne-Cecile
    Franchet, Camille
    Moyret-Lalle, Caroline
    Brousset, Pierre
    Puisieux, Alain
    Hoffmann, Jean-Sebastien
    Tissier, Agnes
    FRONTIERS IN CELL AND DEVELOPMENTAL BIOLOGY, 2021, 9
  • [29] Reciprocal regulation of ZEB1 and AR in triple negative breast cancer cells
    Tisheeka R. Graham
    Rami Yacoub
    LaTonia Taliaferro-Smith
    Adeboye O. Osunkoya
    Valerie A. Odero-Marah
    Tongrui Liu
    K. Sean Kimbro
    Dipali Sharma
    Ruth M. O’Regan
    Breast Cancer Research and Treatment, 2010, 123 : 139 - 147
  • [30] ZEB1 induces ROS generation through directly promoting MCT4 transcription to facilitate breast cancer
    Han, Xiao
    Long, Yaping
    Duan, Xianxian
    Liu, Zhanzhao
    Hu, Xiao
    Zhou, Jing
    Li, Ning
    Wang, Yue
    Qin, Junfang
    EXPERIMENTAL CELL RESEARCH, 2022, 412 (02)