Netrin-1 expression confers a selective advantage for tumor cell survival in metastatic breast cancer
Open accessAbstract
Netrin-1, an axon navigation cue was proposed to play a crucial role during colorectal tumorigenesis by regulating apoptosis. The netrin-1 receptors DCC and UNC5H were shown to belong to the family of dependence receptors that share the ability to induce apoptosis in the absence of their ligands. Such a trait confers on these receptors a tumor suppressor activity. Expression of one of these dependence receptors at the surface of a tumor cell is indeed speculated to render this cell dependent on ligand availability for its survival, hence inhibiting uncontrolled cell proliferation or metastasis. Consequently, it is a selective advantage for a tumor cell to lose this dependence receptor activity, as previously described with losses of DCC and UNC5H expression in human cancers. However, the model predicts that a similar advantage may be obtained by gaining autocrine expression of the ligand. We describe here that, unlike human nonmetastatic breast tumors, a large fraction of metastatic breast cancers overexpress netrin-1. Moreover, we show that netrin-1-expressing mammary metastatic tumor cell lines undergo apoptosis when netrin-1 expression is experimentally decreased or when decoy soluble receptor ectodomains are added. Such treatments prevent metastasis formation both in a syngenic mouse model of lung colonization of a mammary cancer cell line and in a model of spontaneous lung metastasis of xenografted human breast tumor. Thus, netrin-1 expression observed in a large fraction of human metastatic breast tumors confers a selective advantage for tumor cell survival and potentially represents a promising target for alternative anticancer therapeutic strategies.
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Neoplastic cells often escape dependence receptor-mediated RCD by upregulating expression of cognate ligands such as NTN1.
“(1) upregulating the expression of their cognate ligands such as NTN1 [360–362]”
From Molecular mechanisms of cell death: recommendations of the nomenclature committee on cell death 2018. (2018) · cites this paper as [360]
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RetractedDifferential expression of neurogenes among breast cancer subtypes identifies high risk patients
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Dependence receptors – the dark side awakens
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Unraveling the Role of Huntingtin in Breast Cancer Metastasis
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Self-citationRETRACTED: Netrin-1 promotes metastasis of gastric cancer by regulating YAP activity
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Retracted
- Authors
- Fitamant, J., Guenebeaud, C., Coissieux, M.-M., Guix, C., Treilleux, I., Scoazec, J.-Y., Bachelot, T., Bernet, A., & Mehlen, P.
- Affiliations
- Centre National de la Recherche Scientifique (FR)
- Inserm (FR)
- Lyon 1 Université (FR)
- Corresponding author
- Mehlen, Patrick
- ORCID
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2008-03-25
- Volume
- 105
- Issue
- 12
- Pages
- 4850-4855
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC2290782
- OpenAlex
- W1980116118
- Cited by
- 241
- References
- 36
- Citations by year
- 2026: 7 · 2025: 10 · 2024: 12 · 2023: 12 · 2022: 18 · 2021: 10 · 2020: 16 · 2019: 15 · 2018: 17 · 2017: 13 · 2016: 13 · 2015: 11 · 2014: 14 · 2013: 15 · 2012: 13
- FWCI
- 6.49
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- European Commission
- Agence Nationale de la Recherche
- Institut National de la Santé et de la Recherche Médicale
- Ligue Contre le Cancer
- Centre National de la Recherche Scientifique
- Institut National Du Cancer
- Université de Lyon
- Goddard Space Flight Center
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Axon Guidance and Neuronal Signaling
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cell death mechanisms and regulation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mechanisms of cancer metastasis
- Keywords
- netrin-1, metastatic breast cancer, dependence receptors, DCC receptor, apoptosis, tumor cell survival, lung metastasis, tumor suppressor activity, cancer therapy targets
- MeSH terms
- Netrin-1, Animals, Breast Neoplasms, Cell Survival, Female, Humans, Lung Neoplasms, Neoplasm Metastasis, Neoplasm Transplantation, Nerve Growth Factors, Biomarkers, Tumor, Gene Expression Regulation, Neoplastic, Cell Death, Autocrine Communication, Reverse Transcriptase Polymerase Chain Reaction, Tumor Suppressor Proteins, Cell Line, Tumor, Mice
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