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Notch3 Maintains Luminal Phenotype and Suppresses Tumorigenesis and Metastasis of Breast Cancer via Trans-Activating Estrogen Receptor-alpha
Dou, Xiao-Wei1,2; Liang, Yuan-Ke1,2,3; Lin, Hao-Yu1,2,4; Wei, Xiao-Long1,2,5; Zhang, Yong-Qu1,2; Bai, Jing-Wen1,2; Chen, Chun-Fa1,2; Chen, Min2; Du, Cai-Wen6; Li, Yao-Chen1,2; Tian, Jie7; Man, Kwan8; Zhang, Guo-Jun1,2
Source PublicationTHERANOSTICS
2017
Volume7Issue:16Pages:4041-4056
SubtypeArticle
AbstractThe luminal A phenotype is the most common breast cancer subtype and is characterized by estrogen receptor alpha expression (ER alpha). Identification of the key regulator that governs the luminal phenotype of breast cancer will clarify the pathogenic mechanism and provide novel therapeutic strategies for this subtype of cancer. ER alpha signaling pathway sustains the epithelial phenotype and inhibits the epithelial-mesenchymal transition (EMT) of breast cancer. In this study, we demonstrate that Notch3 positively associates with ER alpha in both breast cancer cell lines and human breast cancer tissues. We found that overexpression of Notch3 intra-cellular domain, a Notch3 active form (N3ICD), in ER alpha negative breast cancer cells re-activated ER alpha, while knock-down of Notch3 reduced ER alpha transcript and proteins, with alteration of down-stream genes, suggesting its ability to regulate ER alpha. Mechanistically, our results show that Notch3 specifically binds to the CSL binding element of the ER alpha promoter and activates ER alpha expression. Moreover, Notch3 suppressed EMT, while suppression of Notch3 promoted EMT in cellular assay. Overexpressing N3ICD in triple-negative breast cancer suppressed tumorigenesis and metastasis in vivo. Conversely, depletion of Notch3 in luminal breast cancer promoted metastasis in vivo. Furthermore, Notch3 transcripts were significantly associated with prolonged relapse-free survival in breast cancer, in particular in ER alpha positive breast cancer patients. Our observations demonstrate that Notch3 governs the luminal phenotype via trans-activating ER alpha expression in breast cancer. These findings delineate the role of a Notch3/ER alpha axis in maintaining the luminal phenotype and inhibiting tumorigenesis and metastasis in breast cancer, providing a novel strategy to re-sensitize ER alpha negative or low-expressing breast cancers to hormone therapy.
KeywordNotch3 Estrogen Receptor Alpha Epithelial-mesenchymal Transition Breast Cancer Luminal Phenotype
WOS HeadingsScience & Technology ; Life Sciences & Biomedicine
DOI10.7150/thno.19989
WOS KeywordEPITHELIAL-MESENCHYMAL TRANSITION ; OVARIAN-CANCER ; MUC5AC EXPRESSION ; TUMOR-SUPPRESSOR ; CELL-FATE ; ER-ALPHA ; PATHWAY ; OVEREXPRESSION ; CHEMORESISTANCE ; TRANSCRIPTION
Indexed BySCI
Language英语
Funding OrganizationMajor State Basic Research Development Program of China(2011CB707705) ; Major International Collaborative Research Project of NSFC(81320108015) ; Team project of Guangdong Natural Science Foundation Committee(2016A030312008) ; Guangdong Provincial Key Laboratory on Breast Cancer Diagnosis and Treatment Research
WOS Research AreaResearch & Experimental Medicine
WOS SubjectMedicine, Research & Experimental
WOS IDWOS:000411881900008
Citation statistics
Cited Times:6[WOS]   [WOS Record]     [Related Records in WOS]
Document Type期刊论文
Identifierhttp://ir.ia.ac.cn/handle/173211/20737
Collection中国科学院分子影像重点实验室
Affiliation1.SUMC, Breast Ctr, Canc Hosp, Shantou, Peoples R China
2.SUMC, Canc Hosp, ChangJiang Scholars Lab, Shantou, Peoples R China
3.Univ Groningen, Univ Med Ctr Groningen, Dept Med Oncol, Hanzepl 1, NL-9713 GZ Groningen, Netherlands
4.SUMC, Dept Breast & Thyroid Surg, Affiliated Hosp 1, Shantou, Peoples R China
5.SUMC, Dept Pathol, Canc Hosp, Shantou, Peoples R China
6.SUMC, Canc Hosp, Dept Breast Med Oncol, Shantou, Peoples R China
7.Chinese Acad Sci, Inst Automat, Beijing, Peoples R China
8.Hong Kong Univ Li Ka Tsing, Fac Med, Dept Surg, Hong Kong, Hong Kong, Peoples R China
Recommended Citation
GB/T 7714
Dou, Xiao-Wei,Liang, Yuan-Ke,Lin, Hao-Yu,et al. Notch3 Maintains Luminal Phenotype and Suppresses Tumorigenesis and Metastasis of Breast Cancer via Trans-Activating Estrogen Receptor-alpha[J]. THERANOSTICS,2017,7(16):4041-4056.
APA Dou, Xiao-Wei.,Liang, Yuan-Ke.,Lin, Hao-Yu.,Wei, Xiao-Long.,Zhang, Yong-Qu.,...&Zhang, Guo-Jun.(2017).Notch3 Maintains Luminal Phenotype and Suppresses Tumorigenesis and Metastasis of Breast Cancer via Trans-Activating Estrogen Receptor-alpha.THERANOSTICS,7(16),4041-4056.
MLA Dou, Xiao-Wei,et al."Notch3 Maintains Luminal Phenotype and Suppresses Tumorigenesis and Metastasis of Breast Cancer via Trans-Activating Estrogen Receptor-alpha".THERANOSTICS 7.16(2017):4041-4056.
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