Fig. 3.

MDM2 inhibition and endocrine therapy synergistically reduce proliferation and downregulate hallmark gene sets of cell cycle progression. a Growth inhibition relative to vehicle of escalating doses of NVP-CGM097 (red) and fulvestrant (blue) alone and in combination (purple) b log₂ (combination index) calculated from results in a Values below 0 (equivalent to combination index < 1) indicate synergy. Dose points: NVP-CGM097 × 100 nM; fulvestrant × 0.1 nM. c Proportion of MCF-7 cells staining positive for Annexin V (apoptotic cells) after treatment for 48 h with vehicle (green), 1 μM NVP-CGM097 (red) or the combination of 1 μM NVP-CGM097 and 1 nM fulvestrant (purple). Statistical significance from Tukey’s multiple comparison test is indicated above each column. d Normalised log₂ expression of significant p53 target genes induced by treatment for 48 h with NVP-CGM097 (1 μM, red), fulvestrant (1 nM, blue) and combination (1 μM NVP-CGM097 and 1 nM fulvestrant, purple), averaged by condition, associated with cell cycle, apoptosis and senescence. e Heat map of significant downregulated genes from the E2F targets and G₂/M checkpoint Molecular Signatures Database (MSigDB) gene sets, normalised by gene (row), in MCF-7 cell lines for each condition: vehicle (0.01% DMSO), NVP-CGM097 (1 μM), fulvestrant (1 nM) and combination (1 μM NVP-CGM097 and 1 nM fulvestrant)