Figure 4.

The tipping point of drug resistance process revealed by DNB method. (A) The abrupt increase of the average DNB score clearly signals that there is a tipping point located around 3–4 weeks after the exposure of tamoxifen, after which the system undergoes the drastic transition to the resistance state. (B) The landscape curve of the local DNB method again indicates that 3–4 weeks after the exposure of tamoxifen are the critical transition period from the tamoxifen non-resistance state into a resistance state. (C) Some genes with top significant changes in local DNB scores around the identified transition period (3–4 weeks) are illustrated in three consecutive radar plots, in which the local DNBs generated from case and control samples are showed. The red curve represents the local DNB scores from the case samples while the green curve is that from the control data. At the pre-resistance stage, the DNB scores of case samples are significant. It can be seen that these top significant genes are enriched in pathways closely relevant to breast cancer. Besides, the sensitivity is demonstrated from the comparison between case and control local DNB curves. (D) Based on the mRNA-seq data of MCF-7 breast cancer cells, we illustrate dynamical evolution of the whole gene network (the co-expressed network). DNB genes are intentionally put together. It can be seen that by using DNB, an early-warning signal of the resistance from a network perspective can be detected at 3–4 weeks after the exposure of tamoxifen. The whole dynamics across the 12 weeks are given in Supplementary Figure S4.