Notch3 Maintains Luminal Phenotype and Suppresses Tumorigenesis and Metastasis of Breast Cancer via Trans-Activating Estrogen Receptor-α
| Autor: | Yao-Chen Li, Chun-Fa Chen, Jing-Wen Bai, Jie Tian, Cai-Wen Du, Yong-Qu Zhang, Guo-Jun Zhang, Hao-Yu Lin, Yuan-Ke Liang, Xiao-Long Wei, Kwan Man, Min Chen, Xiao-Wei Dou |
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| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
medicine.medical_specialty Receptor ErbB-2 ER-ALPHA luminal phenotype epithelial-mesenchymal transition Medicine (miscellaneous) Estrogen receptor Breast Neoplasms Biology medicine.disease_cause OVARIAN-CANCER Metastasis PATHWAY 03 medical and health sciences breast cancer Breast cancer estrogen receptor alpha Internal medicine medicine Humans TUMOR-SUPPRESSOR TRANSCRIPTION Epithelial–mesenchymal transition skin and connective tissue diseases Receptor Notch3 Pharmacology Toxicology and Pharmaceutics (miscellaneous) CHEMORESISTANCE Notch3 estrogen receptor α medicine.disease Gene Expression Regulation Neoplastic Cell Transformation Neoplastic 030104 developmental biology Endocrinology Receptors Estrogen Cancer research Female OVEREXPRESSION Signal transduction CELL-FATE Carcinogenesis Ovarian cancer Estrogen receptor alpha Research Paper MUC5AC EXPRESSION |
| Zdroj: | Theranostics, 7(16), 4041-4056. IVYSPRING INT PUBL Theranostics |
| ISSN: | 1838-7640 |
| DOI: | 10.7150/thno.19989 |
| Popis: | The luminal A phenotype is the most common breast cancer subtype and is characterized by estrogen receptor α expression (ERα). 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. ERα 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 ERα 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 ERα negative breast cancer cells re-activated ERα, while knock-down of Notch3 reduced ERα transcript and proteins, with alteration of down-stream genes, suggesting its ability to regulate ERα. Mechanistically, our results show that Notch3 specifically binds to the CSL binding element of the ERα promoter and activates ERα 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 ERα positive breast cancer patients. Our observations demonstrate that Notch3 governs the luminal phenotype via trans-activating ERα expression in breast cancer. These findings delineate the role of a Notch3/ERα axis in maintaining the luminal phenotype and inhibiting tumorigenesis and metastasis in breast cancer, providing a novel strategy to re-sensitize ERα negative or low-expressing breast cancers to hormone therapy. |
| Databáze: | OpenAIRE |
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