Moreover, BRD4 pharmacological inhibition using two BET inhibitors (JQ1 and GSK525762A) induced a dose-dependent reduction in BRCA1 and RAD51 levels and is able to hinder homologous recombination-mediated DNA damage repair, generating a BRCAness phenotype in TNBC cells.
<b>Results:</b> Head-to-head comparison showed that <sup>89</sup>Zr-transferrin targets TNBC tumors significantly better (<i>P</i> < 0.05-0.001) than <sup>18</sup>F-FDG through PET imaging and biodistribution studies in MDA-MB-231 and MDA-MB-157 xenografts and a patient-derived xenograft model of TNBC. c-Myc and <i>TfR</i> gene expression was decreased upon treatment with BRD4 inhibitors and <i>c-MYC</i> small interfering RNA (<i>P</i> < 0.01-0.001 for responding cell lines), compared with vehicle treatment.
Here, using both hormone-sensitive and triple-negative breast cancer (TNBC) model systems, we systematically altered EMT transcriptional profiles by manipulating individual BET proteins and found that BRD2 positively regulates EMT, whereas BRD3 and BRD4 repress this program.
Here, we report a thienodiazepine-based bivalent BrD inhibitor, MS645, that affords spatially constrained tandem BrD inhibition and consequently sustained repression of BRD4 transcriptional activity in blocking proliferation of solid-tumor cells including a panel of triple-negative breast cancer (TNBC) cells.