ArticleOncogenesis2016
Epigenetic suppression of neprilysin regulates breast cancer invasion.
Article in Oncogenesis, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 14 papers, 1 of them a synthesis that pooled it.
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The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
14 citing papers in PubMed, 1 synthesis or guideline pooled it, 26 citations in OpenAlex.
- Prognostic DNA methylation markers for hormone receptor breast cancer: a systematic review.Breast cancer research : BCR · 2020Pooled it
- Maternal Overweight Downregulates MME (Neprilysin) in Feto-Placental Endothelial Cells and in Cord Blood.International journal of molecular sciences · 2020Trial
- Single cell spatial transcriptomics track the evolutionary hierarchy and microenvironment remodeling during breast carcinoma invasion.Nature communications · 2026Article
- Article
- Evaluation of the CIB1R peptide derived from the cytoplasmic domain of neprilysin on cell migration in anFrontiers in oncology · 2026Article
- HSP90α and KLK6 Co-Regulate Stress-Induced Prostate Cancer Cell Motility.bioRxiv : the preprint server for biology · 2025Article
- Neprilysin regulates the progression of glioblastoma: an in-vitro study using siRNA mediated gene silencing and HDAC1 mediated upregulation of neprilysin in U87 MG cells.Molecular and cellular biochemistry · 2025Article
- Synthetic Reader-Actuators Targeted to Polycomb-Silenced Genes Block Triple-Negative Breast Cancer Proliferation and Invasion.GEN biotechnology · 2023Article
- Alpha Ketoglutarate Downregulates the Neutral Endopeptidase and Enhances the Growth Inhibitory Activity of Thiorphan in Highly Aggressive Osteosarcoma Cells.Molecules (Basel, Switzerland) · 2022Article
- Narrative review in the current role of angiotensin receptor-neprilysin inhibitors.Annals of translational medicine · 2021Review
- Alterations in Gene Expression of Renin-Angiotensin System Components and Related Proteins in Colorectal Cancer.Journal of the renin-angiotensin-aldosterone system : JRAAS · 2021Article
- The circulating form of neprilysin is not a general biomarker for overall survival in treatment-naïve cancer patients.Scientific reports · 2019Article
- Potential Expanded Indications for Neprilysin Inhibitors.Current heart failure reports · 2017Review
- Long-term neprilysin inhibition - implications for ARNIs.Nature reviews. Cardiology · 2017Review
Corrections and comments
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Authors and funding
11 authors at 1 institution in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
In women, invasive breast cancer is the second most common cancer and the second cause of cancer-related death. Therefore, identifying novel regulators of breast cancer invasion could lead to additional biomarkers and therapeutic targets. Neprilysin, a cell-surface enzyme that cleaves and inactivates a number of substrates including endothelin-1 (ET1), has been implicated in breast cancer, but whether neprilysin promotes or inhibits breast cancer cell progression and metastasis is unclear. Here, we asked whether neprilysin expression predicts and functionally regulates breast cancer cell invasion. RT-PCR and flow cytometry analysis of MDA-MB-231 and MCF-7 breast cancer cell lines revealed decreased neprilysin expression compared with normal epithelial cells. Expression was also suppressed in invasive ductal carcinoma (IDC) compared with normal tissue. In addition, in vtro invasion assays demonstrated that neprilysin overexpression decreased breast cancer cell invasion, whereas neprilysin suppression augmented invasion. Furthermore, inhibiting neprilysin in MCF-7 breast cancer cells increased ET1 levels significantly, whereas overexpressing neprilysin decreased extracellular-signal related kinase (ERK) activation, indicating that neprilysin negatively regulates ET1-induced activation of mitogen-activated protein kinase (MAPK) signaling. To determine whether neprilysin was epigenetically suppressed in breast cancer, we performed bisulfite conversion analysis of breast cancer cells and clinical tumor samples. We found that the neprilysin promoter was hypermethylated in breast cancer; chemical reversal of methylation in MDA-MB-231 cells reactivated neprilysin expression and inhibited cancer cell invasion. Analysis of cancer databases revealed that neprilysin methylation significantly associates with survival in stage I IDC and estrogen receptor-negative breast cancer subtypes. These results demonstrate that neprilysin negatively regulates the ET axis in breast cancer, and epigenetic suppression of neprilysin in invasive breast cancer cells enables invasion. Together, this implicates neprilysin as an important regulator of breast cancer invasion and clarifies its utility as a potential biomarker for invasive breast cancer.
Identifiers
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.