ArticleOncotarget2014
TBX2 represses CST6 resulting in uncontrolled legumain activity to sustain breast cancer proliferation: a novel cancer-selective target pathway with therapeutic opportunities.
Article in Oncotarget, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 25 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.
Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.
Who cites it
25 citing papers in PubMed, 1 synthesis or guideline pooled it, 44 citations in OpenAlex.
- Clinicopathologic significance of legumain overexpression in cancer: a systematic review and meta-analysis.Scientific reports · 2015Pooled it
- Research on the role and mechanisms of Cystatin 6 in disease pathosis and development.Frontiers in molecular biosciences · 2026Review
- Cystatin 6 (CST6) and Legumain (LGMN) are potential mediators in the pathogenesis of preeclampsia.Scientific reports · 2025Article
- Exploring the oncogenic roles of T-box transcription factor TBX2 and its potential as a therapeutic target.Biochemical Society transactions · 2025Review
- Theranostic Fluorescent Probes.Chemical reviews · 2024Review
- Type 2 Cystatins and Their Roles in the Regulation of Human Immune Response and Cancer Progression.Cancers · 2023Review
- CST6 suppresses osteolytic bone disease in multiple myeloma by blocking osteoclast differentiation.The Journal of clinical investigation · 2022Article
- An infection-induced oxidation site regulates legumain processing and tumor growth.Nature chemical biology · 2022Article
- TBX2 acts as a potent transcriptional silencer of tumour suppressor genes through interaction with the CoREST complex to sustain the proliferation of breast cancers.Nucleic acids research · 2022Article
- Review
- ELK1 Enhances Pancreatic Cancer Progression Via LGMN and Correlates with Poor Prognosis.Frontiers in molecular biosciences · 2021Article
- CST6 protein and peptides inhibit breast cancer bone metastasis by suppressing CTSB activity and osteoclastogenesis.Theranostics · 2021Article
- Review
- Haplotype-resolved and integrated genome analysis of the cancer cell line HepG2.Nucleic acids research · 2019Article
- Review: Precision medicine and driver mutations: Computational methods, functional assays and conformational principles for interpreting cancer drivers.PLoS computational biology · 2019Review
- TBX2 overexpression promotes proliferation and invasion through epithelial-mesenchymal transition and ERK signaling pathway.Experimental and therapeutic medicine · 2019Article
- Article
- Effect of silencing the T‑Box transcription factor TBX2 in prostate cancer PC3 and LNCaP cells.Molecular medicine reports · 2017Article
- Low-level internalization of cystatin E/M affects legumain activity and migration of melanoma cells.The Journal of biological chemistry · 2017Article
- The Identification of Macrophage-enriched Glycoproteins Using Glycoproteomics.Molecular & cellular proteomics : MCP · 2017Article
Corrections and comments
PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.
Authors and funding
19 authors at 2 institutions in 2 countries.
Funding
Abstract
TBX2 is an oncogenic transcription factor known to drive breast cancer proliferation. We have identified the cysteine protease inhibitor Cystatin 6 (CST6) as a consistently repressed TBX2 target gene, co-repressed through a mechanism involving Early Growth Response 1 (EGR1). Exogenous expression of CST6 in TBX2-expressing breast cancer cells resulted in significant apoptosis whilst non-tumorigenic breast cells remained unaffected. CST6 is an important tumor suppressor in multiple tissues, acting as a dual protease inhibitor of both papain-like cathepsins and asparaginyl endopeptidases (AEPs) such as Legumain (LGMN). Mutation of the CST6 LGMN-inhibitory domain completely abrogated its ability to induce apoptosis in TBX2-expressing breast cancer cells, whilst mutation of the cathepsin-inhibitory domain or treatment with a pan-cathepsin inhibitor had no effect, suggesting that LGMN is the key oncogenic driver enzyme. LGMN activity assays confirmed the observed growth inhibitory effects were consistent with CST6 inhibition of LGMN. Knockdown of LGMN and the only other known AEP enzyme (GPI8) by siRNA confirmed that LGMN was the enzyme responsible for maintaining breast cancer proliferation. CST6 did not require secretion or glycosylation to elicit its cell killing effects, suggesting an intracellular mode of action. Finally, we show that TBX2 and CST6 displayed reciprocal expression in a cohort of primary breast cancers with increased TBX2 expression associating with increased metastases. We have also noted that tumors with altered TBX2/CST6 expression show poor overall survival. This novel TBX2-CST6-LGMN signaling pathway, therefore, represents an exciting opportunity for the development of novel therapies to target TBX2 driven breast cancers.
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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.