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Updated: Jun 26, 2026
Detection of Alternative Splicing During Epithelial-Mesenchymal Transition
Published on: October 9, 2014
Tumoral switch in NUMB splicing changes essential transcription pathways and induces malignant properties in tumour
José Manuel García-Heredia1,2,3, Sara M Ortega-Campos4,5, Amancio Carnero6,7
1Instituto de Biomedicina de Sevilla (IBIS)/HUVR/CSIC/Universidad de Sevilla, Hospital Universitario Virgen del Rocío, Ed. IBIS, Avda. Manuel Siurot S/N, Seville, 41013, Spain. jmgheredia@us.es.
Background:
Emerging evidence indicates that cancer is associated with widespread splicing alterations that generate tumour-specific isoforms. One example is NUMB, an evolutionarily conserved adaptor protein, which produces four isoforms (p72, p71, p66, and p65) through alternative splicing of exons 3 and 9. Although traditionally considered as a tumour suppressor, NUMB has also been reported as an oncogene. We propose that this dual role reflects isoform-specific expression.
Results:
Using public databases, we identify a tumour-associated switch in NUMB isoform expression: p72 and p71 are upregulated in tumours, whereas p66 and p65 are more highly expressed in non-tumour tissues. These isoforms show distinct associations with key cellular processes. NUMBL, a NUMB homolog, displays expression patterns similar to p65. We further identify two transcriptional clusters: one characterised by high expression of p72 and p71, and the other by enhanced p66/p65/NUMBL expression. These clusters exhibit differential associations with Notch, WNT/β-catenin, Hedgehog, and Hippo signalling pathways, suggesting isoform-specific regulatory roles. In breast cancer cell lines, we develop a NUMB-score based on isoform expression, which classifies cell lines into biologically distinct groups. The p72/p71-enriched group shows distinct signatures, pathway activity, and drug sensitivity. Application of this score to TCGA-BRCA samples reveals a significant link between high NUMB-score and poor survival, as confirmed by Kaplan-Meier analysis.
Conclusions:
We find that NUMB emerges as a potential oncogenic contributor and biomarker in the context of splicing-based precision oncology, highlighting Isoform-specific expression as a clinical determinant of tumour behaviour, pathway activity, and therapeutic response.
Insights
NUMB protein isoforms show distinct expression patterns in tumors versus normal tissues. This isoform-specific expression influences cancer pathways and can serve as a biomarker for patient survival and therapeutic response in precision oncology.
Area of Science:
- Molecular Biology
- Cancer Research
- Genomics
Background:
- Cancer is linked to widespread splicing alterations creating tumor-specific protein isoforms.
- The NUMB protein, involved in cell processes, exhibits four isoforms (p72, p71, p66, p65) due to alternative splicing.
- NUMB's role as both a tumor suppressor and oncogene may be explained by isoform-specific expression.
Purpose of the Study:
- To investigate the tumor-associated expression patterns of NUMB isoforms.
- To explore the functional and clinical implications of NUMB isoform-specific expression in cancer.
- To develop a biomarker based on NUMB isoform expression for predicting patient outcomes.
Main Methods:
- Analysis of public databases to identify NUMB isoform expression patterns in tumor vs. non-tumor tissues.
- Identification of transcriptional clusters associated with specific NUMB isoform expression profiles.
- Development and application of a NUMB-score in breast cancer cell lines and TCGA-BRCA patient samples.
Main Results:
- A switch in NUMB isoform expression was identified: p72/p71 upregulated in tumors, p66/p65 in non-tumors.
- Distinct NUMB isoform clusters correlated with differential activity in key signaling pathways (Notch, WNT, Hedgehog, Hippo).
- A NUMB-score effectively classified breast cancer cell lines and linked high scores to poor survival in TCGA-BRCA patients.
Conclusions:
- NUMB isoform-specific expression is a critical determinant of tumor behavior, pathway activity, and therapeutic response.
- NUMB isoforms represent potential oncogenic contributors and biomarkers in splicing-based precision oncology.
- Understanding NUMB isoform dynamics offers insights into cancer progression and personalized treatment strategies.
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