Fig. 6. Targeted POLR2A inhibition selectively suppresses the growth of wild type cells derived POLR2A^loss tumours.

a, A schematic illustration of the tumours established by implanting MDA-MB-453 (TP53^mut, POLR2A^loss) cells on the left and MDA-MB-231 (TP53^mut, POLR2A^neutral) cells on the right 4^th inguinal mammary fat pads. b, An illustration of the treatment intervals. The mice were injected with the various treatments twice a week. c-e, Growth curves (c), weight (d), and gross images (e) of tumours derived from POLR2A^loss and POLR2A^neutral human TNBC cells with various treatments. The data indicate that tumours with POLR2A^loss are highly sensitive and vulnerable to further POLR2A inhibition. Error bars denote mean ± s.d. In c, the p values for comparisons of siPol2@NPs versus Saline and siPol2@NPs versus f-siPol2 are 0.0114 (indicated in c) and 0.0061, respectively. The statistical significance was assessed by one-way ANOVA with a Fisher’s LSD post hoc test for c or Dunnett’s post hoc test for d. The biologically independent sample size n=6. Scale bar: 2 cm. f-g, Immunofluorescence staining (f) of POLR2A^loss tumours and quantitative data of POLR2A expression (g) in tumours with various treatments (n=3 independent experiments with 3 replicates in each experiment). The statistical significance was assessed by one-way ANOVA with a Dunnett’s post hoc test. h-i, Protein level of POLR2A (h) and H&E staining (i) of the aforementioned POLR2A^loss tumours. The experiments were repeated three times independently. In h, two representative samples for each treatment are shown. Scale bar: 50 μm. Error bars denote mean ± s.d.; *: p < 0.05; and ***, p < 0.001.