Project description:Sepantronium bromide (YM155), a transcriptional inhibitor of anti-apoptotic protein survivin, is considered as a potential drug candidate for triple negative breast cancers (TNBC). Regardless of its excellent performance in pre-clinical models of TNBC, in patients, this drug was unable to outperform the standard chemotherapy docetaxel. The goal of this study was to identify the pathways/molecules affected by YM155 in TNBC cell lines. Detailed biochemical analysis of the paired YM155-sensitive and resistant cell lines indicates that induction of mitochondrial oxidative stress is a first-line response to the drug, ultimately leading to growth inhibition and induction of cell death. Multiple pathways involved in dampening oxidative stress-induced damages are differentially regulated in YM155-resistant cells. Furthermore, the emergence of YM155 resistance is associated with an extensive transcriptional reprogramming and alteration of many more biological pathways in addition to those identified by biochemical assays. Molecules associated with these biological pathways will potentially serve as biomarkers predicting YM155 sensitivity in TNBC cells.
Project description:Precision Run-On Sequencing (PRO-seq) was performed on triple negative breast cancer (TNBC) cell lines and drug resistant cell lines to determine the epigenetic factors that contribute to TNBC subtypes and drug resistance.
Project description:Our preliminary data found that TNBC cells with Chrom 17p loss are more resistant to chemotherapy drug treatment, compare to cell with 17p intact.To investigate the role of cancer stemness, weg performed this gene expression profiling analysis
Project description:Our preliminary data found that TNBC cells with Chrom 17p loss are more resistant to chemotherapy drug treatment, compare to cell with 17p intact.To investigate the role of cancer stemness, weg performed this gene expression profiling analysis
Project description:Gene expression profiles were performed on MDA-MB-231 TNBC cell line treated with entinostast, all-trans retinoic acid (ATRA), and doxorubicin as single, double, and triple combinations using Illumina. Treatment signatures were made from each drug treatment and integrated to find a comprehensive view of changes associated with the epigenetic, differentiation and chemotherapy combination
Project description:Triple-negative breast cancer (TNBC) initially exhibits a robust response to chemotherapy; however paradoxically, the treatment enriches a population of drug-tolerant persister (DTP) cells, which are known to drive therapy resistance. Therefore, it is crucial to, foremost, identify and subsequently target the signaling pathways implicated in therapy-induced drug resistance and the emergence of DTP cells. In this study, by combining the use of human TNBC cell lines, 3D patient-derived organoid models, and in vivo xenograft models, we identified activation of the Wnt/β-catenin signaling pathway as a common mechanism underlying early DTP cell(s) enrichment in response to different chemotherapeutic agents. Live-cell imaging using Wnt-reporter TNBC cell lines validated diverse patterns of Wnt-transcriptional enrichment, encompassing both intrinsic selection and acquired de novo activation in response to chemotherapy treatment. Purification of differential Wnt-transcriptional populations revealed that post-treatment WntLow cells succumb to apoptosis, while, in contrast, chemotherapy-treated Wnt-active (WntHigh) cells adopt stem cell-like traits, exhibit reduced proliferation, and are, in turn, refractory to treatment. The transition to a post-treatment WntHigh state is orchestrated by increased expression of Wnt ligands, R-spondins, and factors facilitating Wnt ligand secretion, such as PORCN. Consequently, genetic or concomitant - but not sequential - pharmacological inhibition of Wnt ligand secretion alongside chemotherapy prevents treatment-induced WntHigh enrichment and sensitizes TNBC tumors to chemotherapy. Taken together, these observations provide a strong rationale for testing dual treatment comprising chemotherapy and Wnt ligand secretion inhibitors in clinical trials, extending to all TNBC patients.
