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Background <p>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.</p> Results <p>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.</p> Conclusions <p>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.</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年8月4日

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  • Djorkaeff O. Fontinele,
  • Klaus A. R. Reiniger,
  • Arthur H. D. Azevedo,
  • Joao Paulo M. S. Lima,
  • Shantanu Gupta

摘要

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.