Project description:Estrogen signaling pathway is critical for breast cancer development and has remained the major adjuvant therapeutic target for this disease. Tamoxifen has been used in clinic for many years to treat ER-positive breast cancer. However a great many (30%) suffer relapse due to drug resistance. In this study, the bromodomain inhibitor JQ1 was found to down-regulate ERalpha gene expression and have anti-tumor effect in cultured tamoxifen-resisant breast cancer cells. We used microarrays to detail the global programme of gene expression in tamoxifen-resistant MCF7 cells treated with the bromodomain inhibitor JQ1. Tamoxifen-resistant breast cancer MCF7 cells were treated with DMSO (vehicle) or JQ1 (0.2 uM) for 24 hours before total RNA was purified for microarray. Each sample was triplicated.
Project description:Type II testicular germ cell cancers (GCC) are the most frequently diagnosed tumors in young men (20 - 40 years) and are classified as seminoma or non-seminoma. GCCs are commonly treated by orchiectomy and chemo- or radiotherapy. However, a subset of metastatic non-seminomas display only incomplete remission or relapse and require novel treatment options. Recent studies have shown effective application of the small-molecule inhibitor JQ1 in tumor therapy, which interferes with the function of bromodomain and extra-terminal (BET)-proteins. Here, we demonstrate that upon JQ1 doses ≥ 250 nM GCC cell lines and Sertoli cells display compromised survival and induction of cell cycle arrest. JQ1 treated GCC cell lines display upregulation of genes indicative for DNA damage and a cellular stress response. Additionally, downregulation of pluripotency factors and induction of mesodermal differentiation was detected. GCCs xenografted in vivo showed a reduction in tumor size, proliferation and angiogenesis when subjected to JQ1 treatment. The combination of JQ1 and the histone deacetylase inhibitor romidepsin further enhanced the apoptotic effect in vitro and in vivo. Thus, we propose that JQ1 alone, or in combination with romidepsin may serve as a novel therapeutic option for GCCs.
Project description:The bromodomain inhibitor JQ1 and the histone deacetylase inhibitor panobinostat induce synergistic anticancer effects We analyzed whether JQ1 and panobinostat synergistically modulate gene expression Neuroblastoma SK-N-BE(2) cells were treated with vehicle control, 1 microM JQ1, 10 nM panobinostat, or combination of JQ1 and panobinostat for 6 hours, and subjected to differential gene expression studies with Affymetrix microarrays.