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:Model for the activation of SLUG, SIP1, TWIST1, and NF-κB (subunits p50 and p65). The model exhibits two stationary states (bistability), each corresponding to the gene expression profiles we determined from HER2+ and TNBC breast cancer cell lines.
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:Triple-negative breast cancer (TNBC) is an aggressive subtype of breast cancer characterized by a poor prognosis owing to the lack of therapeutic targets, including hormone receptors and HER2. Systemic chemotherapy remains the primary treatment option; however, its efficacy is frequently limited by chemotherapy resistance, a substantial challenge in clinical management. In the present study, we aimed to develop a novel anticancer drug that overcomes chemotherapy resistance in TNBC. First, chemotherapy-resistant MDA-MB-468 cells derived from TNBC were developed via long-term exposure to adriamycin or paclitaxel. Compared with wild-type cells, these resistant cells exhibited reduced sensitivity to paclitaxel, adriamycin, and eribulin in the viability assays. Various compounds were screened for their cell growth-inhibitory activity against these resistant cells to identify novel therapeutic agents; ZSTK3744 was a promising candidate and showed significant anti-tumor activity in vitro and in vivo. Mechanistically, ZSTK3744 upregulated CYP1A1, CYP1B1, and TIPARP expression in MDA-MB-468 cells but exhibited no cell growth-inhibitory activity in aryl hydrocarbon receptor (AhR) knockout cells, indicating that ZSTK3744 act as an AhR agonist. Notably, ZSTK3744 demonstrated superior tumor inhibition and lower pulmonary toxicity in ex vivo and in vivo models than other AhR agonists. These results suggest that ZSTK3744 combines robust cell growth-inhibitory activity with a favorable safety profile. In conclusion, ZSTK3744 is a promising candidate for overcoming chemotherapy resistance in TNBC, addressing the urgent need for more effective treatment options for this aggressive cancer subtype. This study represents the first demonstration of the anti-tumor activity of an AhR agonist on chemotherapy-resistant TNBC.
Project description:Triple-negative breast cancer (TNBC) is an aggressive subtype of breast cancer characterized by a poor prognosis owing to the lack of therapeutic targets, including hormone receptors and HER2. Systemic chemotherapy remains the primary treatment option; however, its efficacy is frequently limited by chemotherapy resistance, a substantial challenge in clinical management. In the present study, we aimed to develop a novel anticancer drug that overcomes chemotherapy resistance in TNBC. First, chemotherapy-resistant MDA-MB-468 cells derived from TNBC were developed via long-term exposure to adriamycin or paclitaxel. Compared with wild-type cells, these resistant cells exhibited reduced sensitivity to paclitaxel, adriamycin, and eribulin in the viability assays. Various compounds were screened for their cell growth-inhibitory activity against these resistant cells to identify novel therapeutic agents; ZSTK3744 was a promising candidate and showed significant anti-tumor activity in vitro and in vivo. Mechanistically, ZSTK3744 upregulated CYP1A1, CYP1B1, and TIPARP expression in MDA-MB-468 cells but exhibited no cell growth-inhibitory activity in aryl hydrocarbon receptor (AhR) knockout cells, indicating that ZSTK3744 act as an AhR agonist. Notably, ZSTK3744 demonstrated superior tumor inhibition and lower pulmonary toxicity in ex vivo and in vivo models than other AhR agonists. These results suggest that ZSTK3744 combines robust cell growth-inhibitory activity with a favorable safety profile. In conclusion, ZSTK3744 is a promising candidate for overcoming chemotherapy resistance in TNBC, addressing the urgent need for more effective treatment options for this aggressive cancer subtype. This study represents the first demonstration of the anti-tumor activity of an AhR agonist on chemotherapy-resistant TNBC.
