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Peer-reviewedCC BY 4.0Cancers

Prognostic Significance of RAN Expression and RAN-Associated Pathways in Breast Cancer: A Systematic Review and Exploratory Meta-Analysis

  • Mohamed El-Tanani1
  • Syed Arman Rabbani1
  • Mohamedanas Mohamedfaruk Patni2
  • Rasha Aziz Attia Salama2
  • Adil Farooq Wali1
  • Riham A. Ibrahim2
  • Yahia El-Tanani3
  • Mohammad Isreb4
4 affiliations
  1. 1RAK College of Pharmacy, RAK Medical and Health Sciences University, Ras Al Khaimah 11172, United Arab Emirates
  2. 2RAK College of Medical Sciences, RAK Medical and Health Sciences University, Ras Al Khaimah 11172, United Arab Emirates
  3. 3Royal Cornwall Hospitals, NHS Trust, Treliske, Truro TR1 3LJ, UK
  4. 4School of Pharmacy and Medical Sciences, University of Bradford, Bradford BD7 1DP, UK
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Abstract

Background: RAN is a small GTPase that regulates nucleocytoplasmic transport, mitotic spindle assembly and chromosome segregation. Experimental studies implicate increased RAN pathway activity in breast cancer proliferation, invasion, metastasis and treatment resistance, whereas clinical studies have primarily measured tumour RAN protein or mRNA expression. The independence and quantitative consistency of this clinical evidence have not been systematically assessed. Methods: PubMed, Embase, Scopus and Web of Science were searched from inception to 1 September 2026 using separate direct RAN and pathway extension strategies. Two reviewers independently screened titles/abstracts and full texts, with disagreements resolved by consensus. One reviewer extracted data using a piloted template and a second reviewer checked every entry; discrepancies were resolved by consensus. Cohort overlap was assessed at institutional cohort and GEO accession levels. Published survival effect estimates were extracted for direct protein expression studies, and unique GEO datasets were reanalysed using a prespecified within-cohort median RAN cut-off and univariable Cox regression. Endpoint-specific random-effects models used restricted maximum likelihood with Hartung–Knapp confidence intervals. Direct evidence measured RAN protein or mRNA; canonical axis evidence assessed established RAN-dependent components or predefined signatures; peripheral/historical links based on nomenclature, paralogy or earlier interaction evidence were contextual only. QUIPS and QUADAS-2 were applied separately, and certainty was assessed using GRADE guidance adapted for prognostic factor research. Results: The eight database exports contained 891 records. After removal of 352 duplicates, 539 unique records were screened; 23 full-text reports were assessed, and 15 clinical publications were included. Six publications were classified as direct RAN, seven as canonical RAN-axis evidence and two as peripheral/historical RAN-associated evidence. The primary protein evidence comprised one Liverpool estimate (Liverpool cohort n = 288; reported Cox RR 12.53, 95% CI 3.95–39.76) and Sheng et al. (multivariable n = 123; HR 2.72, 95% CI 1.15–6.42); these were displayed separately. Across three unique GEO cohorts per endpoint, pooled HRs for high versus low RAN mRNA were 1.38 (95% CI 0.78–2.45; tau-squared = 0) for distant metastasis-free survival, 1.20 (0.36–4.04; tau-squared = 0.1222) for recurrence-free survival, and 1.35 (0.69–2.67; tau-squared = 0) for overall survival. Certainty was low for protein, distant metastasis-free survival, and overall survival, and very low for recurrence-free survival and subgroup findings. Canonical target-specific evidence was not pooled. Conclusions: Adverse protein–survival associations rest on only two independent retrospective cohorts and do not establish a stable effect magnitude or clinical utility; the pooled mRNA findings were inconclusive and the subgroup findings were exploratory. Overlapping cohorts, heterogeneous assays and cut-offs, and the small number of independent datasets limit certainty. The findings support further biomarker development, but prospective multicentre validation and assay standardisation are required before any clinical application.

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Cite

BibTeXRIS
BibTeX
@article{eltanani2026prognostic,
  title = {{Prognostic Significance of RAN Expression and RAN-Associated Pathways in Breast Cancer: A Systematic Review and Exploratory Meta-Analysis}},
  author = {Mohamed El-Tanani and Syed Arman Rabbani and Mohamedanas Mohamedfaruk Patni and Rasha Aziz Attia Salama and Adil Farooq Wali and Riham A. Ibrahim and Yahia El-Tanani and Mohammad Isreb},
  journal = {Cancers},
  year = {2026},
  month = nov,
  doi = {10.3390/cancers18213591},
  url = {https://www.mdpi.com/2072-6694/18/21/3591},
  note = {CC BY 4.0},
}
RIS
TY  - JOUR
TI  - Prognostic Significance of RAN Expression and RAN-Associated Pathways in Breast Cancer: A Systematic Review and Exploratory Meta-Analysis
AU  - Mohamed El-Tanani
AU  - Syed Arman Rabbani
AU  - Mohamedanas Mohamedfaruk Patni
AU  - Rasha Aziz Attia Salama
AU  - Adil Farooq Wali
AU  - Riham A. Ibrahim
AU  - Yahia El-Tanani
AU  - Mohammad Isreb
PY  - 2026
DA  - 2026/11/09
JO  - Cancers
DO  - 10.3390/cancers18213591
UR  - https://www.mdpi.com/2072-6694/18/21/3591
AB  - Background: RAN is a small GTPase that regulates nucleocytoplasmic transport, mitotic spindle assembly and chromosome segregation. Experimental studies implicate increased RAN pathway activity in breast cancer proliferation, invasion, metastasis and treatment resistance, whereas clinical studies have primarily measured tumour RAN protein or mRNA expression. The independence and quantitative consistency of this clinical evidence have not been systematically assessed. Methods: PubMed, Embase, Scopus and Web of Science were searched from inception to 1 September 2026 using separate direct RAN and pathway extension strategies. Two reviewers independently screened titles/abstracts and full texts, with disagreements resolved by consensus. One reviewer extracted data using a piloted template and a second reviewer checked every entry; discrepancies were resolved by consensus. Cohort overlap was assessed at institutional cohort and GEO accession levels. Published survival effect estimates were extracted for direct protein expression studies, and unique GEO datasets were reanalysed using a prespecified within-cohort median RAN cut-off and univariable Cox regression. Endpoint-specific random-effects models used restricted maximum likelihood with Hartung–Knapp confidence intervals. Direct evidence measured RAN protein or mRNA; canonical axis evidence assessed established RAN-dependent components or predefined signatures; peripheral/historical links based on nomenclature, paralogy or earlier interaction evidence were contextual only. QUIPS and QUADAS-2 were applied separately, and certainty was assessed using GRADE guidance adapted for prognostic factor research. Results: The eight database exports contained 891 records. After removal of 352 duplicates, 539 unique records were screened; 23 full-text reports were assessed, and 15 clinical publications were included. Six publications were classified as direct RAN, seven as canonical RAN-axis evidence and two as peripheral/historical RAN-associated evidence. The primary protein evidence comprised one Liverpool estimate (Liverpool cohort n = 288; reported Cox RR 12.53, 95% CI 3.95–39.76) and Sheng et al. (multivariable n = 123; HR 2.72, 95% CI 1.15–6.42); these were displayed separately. Across three unique GEO cohorts per endpoint, pooled HRs for high versus low RAN mRNA were 1.38 (95% CI 0.78–2.45; tau-squared = 0) for distant metastasis-free survival, 1.20 (0.36–4.04; tau-squared = 0.1222) for recurrence-free survival, and 1.35 (0.69–2.67; tau-squared = 0) for overall survival. Certainty was low for protein, distant metastasis-free survival, and overall survival, and very low for recurrence-free survival and subgroup findings. Canonical target-specific evidence was not pooled. Conclusions: Adverse protein–survival associations rest on only two independent retrospective cohorts and do not establish a stable effect magnitude or clinical utility; the pooled mRNA findings were inconclusive and the subgroup findings were exploratory. Overlapping cohorts, heterogeneous assays and cut-offs, and the small number of independent datasets limit certainty. The findings support further biomarker development, but prospective multicentre validation and assay standardisation are required before any clinical application.
SN  - 2072-6694
ER  -