Fig. 2. Type I PRMT inhibition suppresses tumor growth in a subset of TNBC.
a–d, PRMT1 gene expression in TCGA breast cancer datasets (a), METABRIC breast cancer datasets (b), Princess Margaret Hospital PDX datasets (PM-PDXs; c) and Princess Margaret Hospital cell line datasets (PM-cell lines; d). According to PAM50 classification, the cohorts were designated as basal and non-basal subtypes. Gene expression is reported as log2 (TPM + 0.001). In the box plots, the center lines mark the median, the box limits indicate the 25th and 75th percentiles, and the whiskers extend to 1.5× the interquartile range from the 25th and 75th percentiles. The numbers of individuals (n) per group are indicated, and the fold change (FC) values are as labeled. Data were analyzed by unpaired two-tailed Student’s t-test. e, Heat map of responsiveness to MS023 in the indicated cell lines. AAC was calculated from dose–response assays across 17 TNBC cell lines. Data are normalized to DMSO. A higher AAC indicates greater sensitivity. Colored cell lines are studied in more detail in this paper. Data are shown as mean ± s.d.; n = 4. f, Growth curves of Hs578-T and MDA-MB-468 cells treated with MS023 for 5 d. Data are shown as mean ± s.d.; n = 4. g, Immunoblots of MDA-MD-468 and Hs578-T cells following 5 d of treatment with the indicated doses of MS023 and the negative control MS094. Data are representative of n = 3 independent experiments. h, Immunoblots showing the doxycycline-inducible shRNA knockdown of PRMT1 or luciferase control in MDA-MB-468 and Hs578-T cells. Data are representative of n = 3 independent experiments; SDMA, symmetric dimethylarginine; Luc, luciferase. i, Individual tumor growth of the MDA-MB-468 xenograft model with once-daily administration of 60 mg kg–1 MS023 when tumors reach 2 mm in diameter. Data are shown as mean ± s.d.; n = 3. Data were analyzed by two-way ANOVA with Dunnett’s test for multiple comparisons. j, Tumor weight was measured as a surrogate for tumor burden from the control (CTL) and MS023-treated mice. Data are shown as mean ± s.d. (n = 3) and were analyzed by one-way ANOVA with Dunnett’s test. k, Immunoblot of tumor tissue from mice treated with control or MS023 at the experimental endpoint. Data are representative of n = 3 independent technical experiments.