Fig. 3. Notch1 pathway activation confers resistance to targeted therapies in breast cancer, including tamoxifen.
(A) GI50 values for indicated breast cancer cell lines expressing Notch1 ICD or luciferase and treated with the indicated drugs. Data are means ± SD from three experiments. (B) qRT-PCR analysis of Notch1 target genes and mesenchymal markers in breast cancer cell lines expressing Notch1 ICD (red) or luciferase (gray). Data are means ± SD from three experiments. (C) Expression of indicated genes in parental MCF-7 and TamR cells. Data are means ± SD from three experiments. (D) Growth of TamR xenografts treated with tamoxifen, RO4929097 (γ-secretase inhibitor), or the combination. Data are means ± SEM from 9–13 mice per group. Exponential growth curve and two-way ANOVA analyses were performed using GraphPad Prism 6. (E) Kaplan-Meier plot depicting survival in breast cancer patients treated with tamoxifen as a function of Notch1 pathway gene expression signature level (first and third tertiles). P-value denotes significance between drug treated patients in high and low Notch1 groups. (F) Expression heatmap of indicated genes in Notch1 low and high groups from patients in part (E). * p < 0.1; ** p < 0.05; *** p < 0.01