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Peer-reviewedCC BY-NC-NDBMC bioinformatics

miR-206 orchestrates breast cancer radiosensitivity through a SIRT1/p53 feedback loop: a network medicine modelling study.

  • Djorkaeff O Fontinele1
  • Klaus A R Reiniger2
  • Arthur H D Azevedo3
  • Joao Paulo M S Lima1,3
  • Shantanu Gupta4
4 affiliations
  1. 1Bioinformatics Multidisciplinary Environment-BioME - Digital Metropole Institute, Federal University of Rio Grande Do Norte, Natal, RN, 59076550, Brazil.
  2. 2Department of Biophysics and Pharmacology, Federal University of Rio Grande Do Norte, Natal, RN, 59076550, Brazil.
  3. 3Department of Biochemistry, Federal University of Rio Grande Do Norte, Natal, RN, 59076550, Brazil.
  4. 4Bioinformatics Multidisciplinary Environment-BioME - Digital Metropole Institute, Federal University of Rio Grande Do Norte, Natal, RN, 59076550, Brazil. [email protected].
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Abstract

Background

Radiotherapy remains a cornerstone of breast cancer treatment, yet radioresistance limits its efficacy. miR-206 acts as a tumor suppressor by inhibiting SIRT1 and stabilizing p53. However, how these molecular components are organized within larger regulatory networks, and whether such network-level hubs can be therapeutically prioritized, remains unclear.Results

Network modeling predicted a previously unrecognized double-negative feedback loop (miR-206 ⊣ SIRT1 ⊣ p53 → miR-206) that functions as a predicted bistable switch, driving mutually exclusive commitment to either a radiosensitive (apoptotic) or a radioresistant (proliferative) fate. Monte Carlo simulations revealed that opposite perturbations of this circuit consistently drove the system toward the corresponding stable attractor. Edge disruption analysis identified the miR-206/SIRT1 and p53/miR-206 interactions as essential for maintaining bistability, while ATM exerted p53-dependent context-specific effects. Model predictions were consistent with independent experimental observations that miR-206 overexpression suppresses SIRT1, enhances p53 acetylation, and increases radiosensitivity.Conclusions

This network medicine framework identifies the miR-206/SIRT1/p53 bistable switch as a key regulatory module governing cell-fate decisions in breast cancer radioresistance. The model provides a systems-level platform for prioritizing experimentally testable therapeutic strategies to overcome radioresistance.

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Cite

BibTeXRIS
BibTeX
@article{fontinele2026mir206,
  title = {{miR-206 orchestrates breast cancer radiosensitivity through a SIRT1/p53 feedback loop: a network medicine modelling study.}},
  author = {Djorkaeff O Fontinele and Klaus A R Reiniger and Arthur H D Azevedo and Joao Paulo M S Lima and Shantanu Gupta},
  journal = {BMC bioinformatics},
  year = {2026},
  month = aug,
  doi = {10.1186/s12859-026-06592-z},
  url = {https://europepmc.org/article/MED/42968013},
  note = {CC BY-NC-ND},
}
RIS
TY  - JOUR
TI  - miR-206 orchestrates breast cancer radiosensitivity through a SIRT1/p53 feedback loop: a network medicine modelling study.
AU  - Djorkaeff O Fontinele
AU  - Klaus A R Reiniger
AU  - Arthur H D Azevedo
AU  - Joao Paulo M S Lima
AU  - Shantanu Gupta
PY  - 2026
DA  - 2026/08/04
JO  - BMC bioinformatics
DO  - 10.1186/s12859-026-06592-z
UR  - https://europepmc.org/article/MED/42968013
AB  - Background  Radiotherapy remains a cornerstone of breast cancer treatment, yet radioresistance limits its efficacy. miR-206 acts as a tumor suppressor by inhibiting SIRT1 and stabilizing p53. However, how these molecular components are organized within larger regulatory networks, and whether such network-level hubs can be therapeutically prioritized, remains unclear.Results  Network modeling predicted a previously unrecognized double-negative feedback loop (miR-206 ⊣ SIRT1 ⊣ p53 → miR-206) that functions as a predicted bistable switch, driving mutually exclusive commitment to either a radiosensitive (apoptotic) or a radioresistant (proliferative) fate. Monte Carlo simulations revealed that opposite perturbations of this circuit consistently drove the system toward the corresponding stable attractor. Edge disruption analysis identified the miR-206/SIRT1 and p53/miR-206 interactions as essential for maintaining bistability, while ATM exerted p53-dependent context-specific effects. Model predictions were consistent with independent experimental observations that miR-206 overexpression suppresses SIRT1, enhances p53 acetylation, and increases radiosensitivity.Conclusions  This network medicine framework identifies the miR-206/SIRT1/p53 bistable switch as a key regulatory module governing cell-fate decisions in breast cancer radioresistance. The model provides a systems-level platform for prioritizing experimentally testable therapeutic strategies to overcome radioresistance.
SN  - 1471-2105
ER  -