Notch1 signaling regulates the epithelial–mesenchymal transition and invasion of breast cancer in a Slug-dependent manner

Abstract

BackgroundThe epithelial–mesenchymal transition (EMT) is crucial for the invasion and metastasis of breast cancer. However, how Notch signaling regulates the EMT process and invasion in breast cancer remains largely unknown.MethodsThe impact of Notch1 silencing by specific shRNAs on the EMT and invasion of human breast cancer MCF-7 and MDA-MB-231 cells as well as xenografts was tested by western blot, real-time polymerase chain reaction (RT-PCR), immunofluorescence, transwell, and immunohistochemistry assays. The effect of Slug silencing or upregulation on the EMT and invasion of breast cancer cells was analyzed, and the effect of Notch1 signaling on Slug expression was determined by the luciferase reporter assay.ResultsThe Notch1 intracellular domain (N1ICD) and Jagged1 were expressed in breast cancer cells. Notch1 silencing reversed the spontaneous EMT process and inhibited the migration and invasion of breast cancer cells and the growth of xenograft breast cancers. The expression of N1ICD was upregulated significantly by Jagged1-mediated Notch signaling activation. Moreover, Jagged1-mediated Notch signaling promoted the EMT process, migration, and invasion of breast cancer cells, which were abrogated by Notch silencing. Furthermore, the N1ICD positively regulated the Slug expression by inducing Slug promoter activation. Importantly, the knockdown of Slug weakened the invasion ability of breast cancer cells and reversed the Jagged1-induced EMT process with significantly decreased expression of vimentin and increased expression of E-cadherin. In addition, Slug overexpression restored the Notch1 knockdown-suppressed EMT process.ConclusionsOur novel data indicate that Notch signaling positively regulates the EMT, invasion, and growth of breast cancer cells by inducing Slug expression. The Notch1–Slug signaling axis may represent a potential therapeutic target for breast cancer therapy.Electronic supplementary materialThe online version of this article (doi:10.1186/s12943-015-0295-3) contains supplementary material, which is available to authorized users.

Targeting aberrant expression of Notch‐1 in ALDH+ cancer stem cells in breast cancer

“…It has been demonstrated that the metastatic role of Notch‐1 which activates EMT by up‐regulating mesenchymal markers including β‐catenin, snail, slug, vimentin, etc. as well as by down‐regulating epithelial markers, that is E −cadherin in BCa . Our results are consistent with these findings.…”

All-trans-retinoic Acid Modulates the Plasticity and Inhibits the Motility of Breast Cancer Cells

“…In fact, intraperitoneal administration of ATRA at dosages reducing the primary tumor mass causes a significant down-regulation of the NOTCH1, SNAIL, and SLUG mRNAs. 3 These in vivo data are in line with the down-regulation of NOTCH1 and SNAIL observed in SKBR3 cells and the recently reported role of SLUG as a mediator of the EMT and metastatic processes activated by NOTCH1 in xenografts of retinoid-insensitive MDAMB231 cells (61). The antimetastatic properties of ATRA can be exploited at the clinical level for the design of retinoid-based therapeutic strategies aimed at the treatment or chemoprevention of breast cancer.…”

Phosphorylation of Notch1 by Pim kinases promotes oncogenic signaling in breast and prostate cancer cells

“…High Notch1 levels have been linked to poor prognosis in breast cancer [5], where Notch1 has been shown to induce epithelial-to-mesenchymal transition (EMT) [6, 7], upregulate extracellular matrix metalloproteinases [8], and induce a switch to glycolytic metabolism [9], contributing to both tumor initiation and progression. Similarly in prostate cancer, Notch1 supports cancer cell survival and EMT [10].…”