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. Author manuscript; available in PMC: 2015 Oct 23.
Published in final edited form as: Cell. 2014 Oct 23;159(3):499–513. doi: 10.1016/j.cell.2014.09.051

Figure 7. NOTCH3 and STAT1/IRDS cooperate to predict NOTCH target genes and clinical resistance to chemotherapy and RT preferentially in basal-like breast cancers.

Figure 7

Prediction of NOTCH target gene expression by IRDS and NOTCH3/JAG1 in A) primary human tumors and in B) basal-like tumors from the K14Cre;BRCA1F/F;p53F/F conditional knockout mice. For human tumor analysis, the NKI295 series was used. The probability of NOTCH pathway activation as measured by the NOTCH metagene is shown on the y-axis with probabilities for basal (red dots) or non-basal (blue dots) tumors displayed separately. The percentage of tumors with greater than 80% probability of NOTCH activation is inset. A LOWESS regression line (black dashed line) is shown. IRDS and JAG1 were equally divided into low, intermediate, and high values. For mouse tumor analysis, IRDS, NOTCH3, and JAG1 expression were dichotomized into only high and low due to smaller sample size. Mean value is marked by red line. C) Heat map showing probabilities of NOTCH activation and NOTCH3 expression for each patient (columns) in the NKI295 series. All values are scaled between 0 and 1. Hatches below the heat map show status for IRDS(+), NOTCH3(hi), and the indicated molecular subtypes. On the right is Gene Set Analysis for the same TIC signature used in Fig. 5A and compares NOTCH3(hi)/IRDS(+) tumors to those that are NOTCH3(lo) and/or IRDS(−). D) Survival after adjuvant chemotherapy of patients from the NKI295 series stratified by NOTCH3 and IRDS. Overall p-value is shown. E) Hazard ratios and 95% confidence intervals from Cox regression analysis for breast cancer survival using NOTCH3 as a continuous variable, IRDS status (positive vs. negative), and MammaPrint (Mamma) metastasis signature status (positive vs. negative). All patients received adjuvant chemotherapy. Hazard ratio for NOTCH3 is per unit increase in expression. Analyses are also stratified by IRDS status and basal vs. non-basal subtype tumors. Values are not shown if there are too few patients in the group. F) Relapse in irradiated region (local-regional control) after adjuvant RT. G) Hazard ratio from Cox regression for relapse in the Stroma series using stromal RAB27B as a continuous variable. H) Model of the tumor-stroma anti-viral/NOTH3 pathways controlling RT/chemo resistance. See Figure S7.