Notch3 Maintains Luminal Phenotype and Suppresses Tumorigenesis and Metastasis of Breast Cancer via Trans-Activating Estrogen Receptor-?.

ABSTRACT: The luminal A phenotype is the most common breast cancer subtype and is characterized by estrogen receptor ? expression (ER?). 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? 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? 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? negative breast cancer cells re-activated ER?, while knock-down of Notch3 reduced ER? transcript and proteins, with alteration of down-stream genes, suggesting its ability to regulate ER?. Mechanistically, our results show that Notch3 specifically binds to the CSL binding element of the ER? promoter and activates ER? 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? positive breast cancer patients. Our observations demonstrate that Notch3 governs the luminal phenotype via trans-activating ER? expression in breast cancer. These findings delineate the role of a Notch3/ER? axis in maintaining the luminal phenotype and inhibiting tumorigenesis and metastasis in breast cancer, providing a novel strategy to re-sensitize ER? negative or low-expressing breast cancers to hormone therapy.

SUBMITTER: Dou XW 

PROVIDER: S-EPMC5667424 | biostudies-literature | 2017

REPOSITORIES: biostudies-literature