Similar Datasets
Project description:The vast majority of all breast cancers are driven by oestrogen receptor alpha (ERα) activation, and endocrine therapy represents the mainstay treatment for these patients. However, resistance is common and tumours progress despite years of systemic endocrine suppression. Periodic fasting enhances the efficacy of standard endocrine drugs and delay acquired resistance to them, although the underlying mechanisms remain unclear. Here, we show that fasting, in combination with endocrine therapy, induces extensive epigenetic reprogramming in hormone receptor-positive (HR+) breast cancer xenografts, with large-scale activation of glucocorticoid receptor (GR) and progesterone receptor (PR) signalling, and impairment of activator protein-1 (AP-1) family activity. GR-driven gene programs were selectively activated after fasting, and GR knockout perturbed the beneficial effects of fasting in combination with tamoxifen, in vivo. Exogenous administration of GR-ligands fully recapitulated the observed fasting-enhanced anti-oestrogen action, resulting in tumour regression. Finally, elevated progesterone and cortisol levels were detected in the blood of breast cancer patients after fasting, thus providing clinical validation of our animal findings. Our results indicate GR activation to play a pivotal role in fasting’s ability to enhance endocrine drug activity against hormone-receptor positive breast cancer and suggest that corticosteroid administration should be evaluated as an adjuvant to endocrine therapy in this condition.
2025-10-14 | PXD049477 | Pride
Project description:The vast majority of all breast cancers are driven by oestrogen receptor alpha (ERα) activation, and endocrine therapy represents the mainstay treatment for these patients. However, resistance is common and tumours progress despite years of systemic endocrine suppression. Periodic fasting enhances the efficacy of standard endocrine drugs and delay acquired resistance to them, although the underlying mechanisms remain unclear. Here, we show that fasting, in combination with endocrine therapy, induces extensive epigenetic reprogramming in hormone receptor-positive (HR+) breast cancer xenografts, with large-scale activation of glucocorticoid receptor (GR) and progesterone receptor (PR) signalling, and impairment of activator protein-1 (AP-1) family activity. GR-driven gene programs were selectively activated after fasting, and GR knockout perturbed the beneficial effects of fasting in combination with tamoxifen, in vivo. Exogenous administration of GR-ligands fully recapitulated the observed fasting-enhanced anti-oestrogen action, resulting in tumour regression. Finally, elevated progesterone and cortisol levels were detected in the blood of breast cancer patients after fasting, thus providing clinical validation of our animal findings. Our results indicate GR activation to play a pivotal role in fasting’s ability to enhance endocrine drug activity against hormone-receptor positive breast cancer and suggest that corticosteroid administration should be evaluated as an adjuvant to endocrine therapy in this condition.
2025-10-14 | GSE260485 | GEO
Project description:The vast majority of all breast cancers are driven by oestrogen receptor alpha (ERα) activation, and endocrine therapy represents the mainstay treatment for these patients. However, resistance is common and tumours progress despite years of systemic endocrine suppression. Periodic fasting enhances the efficacy of standard endocrine drugs and delay acquired resistance to them, although the underlying mechanisms remain unclear. Here, we show that fasting, in combination with endocrine therapy, induces extensive epigenetic reprogramming in hormone receptor-positive (HR+) breast cancer xenografts, with large-scale activation of glucocorticoid receptor (GR) and progesterone receptor (PR) signalling, and impairment of activator protein-1 (AP-1) family activity. GR-driven gene programs were selectively activated after fasting, and GR knockout perturbed the beneficial effects of fasting in combination with tamoxifen, in vivo. Exogenous administration of GR-ligands fully recapitulated the observed fasting-enhanced anti-oestrogen action, resulting in tumour regression. Finally, elevated progesterone and cortisol levels were detected in the blood of breast cancer patients after fasting, thus providing clinical validation of our animal findings. Our results indicate GR activation to play a pivotal role in fasting’s ability to enhance endocrine drug activity against hormone-receptor positive breast cancer and suggest that corticosteroid administration should be evaluated as an adjuvant to endocrine therapy in this condition.
2025-10-14 | GSE260484 | GEO
Project description:Fasting boosts breast cancer therapy efficacy via glucocorticoid activation
| PRJNA1081869 | ENA
Project description:Fasting boosts breast cancer therapy efficacy via glucocorticoid activation (ChIP-Seq)
| PRJNA1081870 | ENA
Project description:Fasting boosts breast cancer therapy efficacy via glucocorticoid activation (RNA-Seq)
| PRJNA1081872 | ENA
Project description:Approximately 75% of all breast cancers express the oestrogen and/or progesterone receptors. Endocrine therapy is usually effective in these hormone-receptor-positive tumours, but primary and acquired resistance limits its long-term benefit1,2. Here we show that in mouse models of hormone-receptor-positive breast cancer, periodic fasting or a fasting-mimicking diet3-5 enhances the activity of the endocrine therapeutics tamoxifen and fulvestrant by lowering circulating IGF1, insulin and leptin and by inhibiting AKT-mTOR signalling via upregulation of EGR1 and PTEN. When fulvestrant is combined with palbociclib (a cyclin-dependent kinase 4/6 inhibitor), adding periodic cycles of a fasting-mimicking diet promotes long-lasting tumour regression and reverts acquired resistance to drug treatment. Moreover, both fasting and a fasting-mimicking diet prevent tamoxifen-induced endometrial hyperplasia. In patients with hormone-receptor-positive breast cancer receiving oestrogen therapy, cycles of a fasting-mimicking diet cause metabolic changes analogous to those observed in mice, including reduced levels of insulin, leptin and IGF1, with the last two remaining low for extended periods. In mice, these long-lasting effects are associated with long-term anti-cancer activity. These results support further clinical studies of a fasting-mimicking diet as an adjuvant to oestrogen therapy in hormone-receptor-positive breast cancer.
| S-EPMC7881940 | biostudies-literature
Project description:This SuperSeries is composed of the SubSeries listed below.
2023-10-02 | GSE222799 | GEO
Project description:Although immune checkpoint inhibitors improved the clinical outcomes of advanced triple negative breast cancer (TBNC) patients, the response rate remains relatively low. Nigericin is an antibiotic derived from Streptomyces hydrophobicus. We found that nigericin caused cell death in TNBC cell lines MDA-MB-231 and 4T1 by inducing concurrent pyroptosis and apoptosis. As nigericin facilitated cellular potassium efflux, we discovered that it caused mitochondrial dysfunction, leading to mitochondrial ROS production, as well as activation of Caspase-1/GSDMD-mediated pyroptosis and Caspase-3-mediated apoptosis in TNBC cells. Notably, nigericin-induced pyroptosis could amplify the anti-tumor immune response by enhancing the infiltration and anti-tumor effect of CD4+ and CD8+ T cells. Moreover, nigericin showed a synergistic therapeutic effect when combined with anti-PD-1 antibody in TNBC treatment. Our study reveals that nigericin may be a promising anti-tumor agent, especially in combination with immune checkpoint inhibitors for advanced TNBC treatment.
| S-EPMC10296105 | biostudies-literature
Project description:Triple-negative breast cancer (TNBC) accounts for 10% to 20% of newly diagnosed invasive breast cancer. Finding effective targets for chemotherapy-resistant TNBC has proven difficult in part because of TNBC's molecular heterogeneity. We have previously reported that likely because of the antiapoptotic activity of glucocorticoid receptor (GR) in estrogen receptor (ER)-negative breast epithelial and cancer cells, high GR expression/activity in early-stage TNBC significantly correlates with chemotherapy resistance and increased recurrence. We hypothesized that pretreatment with mifepristone, a GR antagonist, would potentiate the efficacy of chemotherapy in GR+ TNBCs by inhibiting the antiapoptotic signaling pathways of GR and increasing the cytotoxic efficiency of chemotherapy.TNBC cell apoptosis was examined in the context of physiologic glucocorticoid concentrations, chemotherapy, and/or pharmacologic concentrations of mifepristone. We used high-throughput live microscopy with continuous recording to measure apoptotic cells stained with a fluorescent dye and Western blot analysis to detect caspase-3 and PARP cleavage. The effect of mifepristone on GR-mediated gene expression was also measured. TNBC xenograft studies were performed in female severe combined immunodeficient (SCID) mice and tumors were measured following treatment with vehicle, paclitaxel, or mifepristone/paclitaxel.We found that although mifepristone treatment alone had no significant effect on TNBC cell viability or clonogenicity in the absence of chemotherapy, the addition of mifepristone to dexamethasone/paclitaxel treatment significantly increased cytotoxicity and caspase-3/PARP cleavage. Mifepristone also antagonized GR-induced SGK1 and MKP1/DUSP1 gene expression while significantly augmenting paclitaxel-induced GR+ MDA-MB-231 xenograft tumor shrinkage in vivo.These results suggest that mifepristone pretreatment could be a useful strategy for increasing tumor cell apoptosis in chemotherapy-resistant GR+ TNBC.
| S-EPMC3860283 | biostudies-literature