Therapeutic targeting of BRCA1 and TP53 mutant breast cancer through mutant p53 reactivation

Loss of BRCA1 sensitizes cells to ZMC1. a Schematic representation of the mechanisms of ZMC1 reactivating mutant p53R175H. b The survival of breast cancer cell line SKBR3 (p53R175H) after knockdown with either control non-target siRNA or BRCA1 siRNA. The cells were treated with 0.01 and 0.005？μM ZMC1. (n？=？4) c Western blotting showed the BRCA1 knockdown by control siRNA (ctrl-siRNA) or BRCA1 siRNA (BRCA1-siRNA) in SKBR3 cells. d The survival of MDA-MB-436 and its two BRCA1-reconstituted cell lines (C6 and C15) after ZMC1 treatment. All the three cell lines were transiently transfected with plasmids expressing human mutant p53R175H (R175H). (n？=？4) e The survival of MDA-MB-436 and its BRCA1-reconstituted cell line (C6) after ZMC1 treatment. Both cell lines were transiently transfected with plasmids expressing human wild type p53 (wtp53). (n？=？4) f Western blotting showed the proteins expression after 1？μM ZMC1 treatment for 6- and 24-hours in MDA-MB-436 and its BRCA1-reconstituted cell line (C6). Both cell lines were transiently transfected with plasmids expressing human p53R175H (R175H). g Quantification of ATM and phospho-ATM (p-ATM) in (f). Student t-test; ***p？<？0.001. Each survival experiment was repeated 2–3 times (Fig. 1b, d and e