Lopes, F. J. P.; Pires, B. R. B.; Lima, A. A. B.; Binato, R.; Abdelhay, E.

Development of subtype heterogeneity in breast cancer requires stochastic transitions between cell types. Here, we sought to characterize how NF-{kappa}B contributes to breast cancer progression. We built a gene regulatory network model and calibrated it to the expression levels of NF-{kappa}B, TWIST1, SIP1, and SLUG in HER2+ and TNBC cell line, using patient and in vitro published data for validation. The model\'s epigenetic landscape exhibits two attractor basins separated by a fluctuation-susceptible slow route. NF-{kappa}B stochastic fluctuations induce irreversible transitions from HER2+ to TNBC basins at different times, increasing heterogeneity. Mutations altering the availability of NF-{kappa}B change the size of the subtype basins, changing the transition probabilities. Our findings enhance the established attractor landscape formulation and deepen understanding of breast cancer heterogeneity.