Fig. 4.

Jun copy number loss causes resistance to entinostat. a Copy number landscape of entinostat-treated MMTV/Neu tumors by arrayCGH. aCGH analysis revealed that a large portion of mouse Chromosome 4 had DNA copy number loss in tumors that progressed while on entinostat. Segments of copy number gains are plotted above the x-axis in red and loss are plotted below the x-axis in green. The frequency of alterations is indicated on the y-axis from 0 to 100%. b Jun gene expression in 27 MMTV/Neu luminal mouse model tumors untreated (N = 6) or treated with entinostat at 12 mg/kg for 3 weeks (N = 6), 6 weeks (N = 5), or until progression (N = 8). Each square represents the relative median transcript abundance (in log2 space) of each signature for untreated or entinostat-treated MMTV/Neu. c, d Sensitivity to entinostat in BT474 or T47D with lentiviral c-Jun knockdown. Jun shRNA treatment makes BT474 or T47D cells resistant toward entinostat as evidenced by an increase in IC₅₀. After BT474 or T47D cells were transfected with lentivirus-mediated Jun shRNA, the cells were incubated in various doses of entinostat for 72 h and then the viability of cells was measured using the MTS assay. Each point represents the mean ± standard deviation of sextuple determinations. Inhibitory concentration (IC) curves are shown with IC₅₀ values in legend