Homo sapiens
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA291216 | ENA |
REPOSITORIES: ENA
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Project description:IKB Kinase beta (IKKB), a key component of the NFKB signalling pathway plays an important role in inflammation and cancer. Here we describe a previously unknown role of the IKKβ/FoxO3a axis in bone metastasis. We found that IKKβ was highly expressed in invasive human breast tumours and that levels of expression were elevated in bone metastasis. Overexpression of IKKβ in parental and bone-tropic human breast cancer cell-lines increased tumour volume, worsened cachexia, promoted osteolysis and increased mortality in adult mice whereas pharmacological inhibition and knockdown of IKKβ were inhibitory. Inhibition of IKKβ in breast cancer cell lines and bone cells stimulated bone formation and reduced tumour growth by a mechanism that was mediated in part, by cytoplasmic sequestering of FoxO3a independently of NFKB inhibition. We conclude that IKβ contributes significantly to the regulation of tumour growth and osteolysis in breast cancer by NFKB dependent and independent mechanisms.
2018-08-29 | GSE71444 | GEO
Project description:BRD4 assembles transcriptional machinery at gene super-enhancer regions and governs the expression of genes that are critical for cancer progression. However, it remains unclear whether BRD4-mediated gene transcription is required for tumor cells to develop drug resistance. Our data show that prolonged treatment of luminal breast cancer cells with AKT inhibitors induces FOXO3a de-phosphorylation, nuclear translocation, and disrupts its association with SIRT6, eventually leading to FOXO3a acetylation as well as BRD4 recognition. Acetylated FOXO3a recognizes the BD2 domain of BRD4, recruits the BRD4/RNAPII complex to the CDK6 gene promoter and induces its transcription. Pharmacological inhibition of either BRD4/FOXO3a association or CDK6 significantly overcomes the resistance of luminal breast cancer cells to AKT inhibitors in vitro and in vivo. Our study reports the involvement of BRD4/FOXO3a/CDK6 axis in AKTi resistance and provides potential therapeutic strategies for treating resistant breast cancer.
2019-02-21 | GSE118148 | GEO
Project description:Cancer cells undergo transcriptional reprogramming to drive tumor progression and metastasis. Here, we identified the transcriptional complex, NELF (Negative elongation factor), as an important regulator of this process. Using cancer cell lines and patient-derived tumor organoids, we demonstrated that loss of NELF inhibits breast cancer tumorigenesis and metastasis. Specifically, we found that epithelial-mesenchymal transition (EMT) and stemness-associated genes are downregulated in NELF-depleted breast cancer cells. Quantitative Multiplexed Rapid Immunoprecipitation Mass spectrometry of Endogenous proteins (qPLEX-RIME) of NELF-E, a key subunit of NELF, reveals significant rewiring of NELF-E-associated chromatin partners as a function of EMT, and further illuminates a co-option of NELF-E with the key EMT transcription factor SLUG. Accordingly, loss of NELF-E led to impaired SLUG binding on chromatin. Through integrative transcriptomic and genomic analyses, we identified the histone acetyltransferase, KAT2B, as a key functional target of NELF-E-SLUG. Genetic and pharmacological inactivation of KAT2B ameliorate expression of critical EMT marker genes, phenocopying NELF ablation. Elevated NELF-E and KAT2B expressions are associated with poorer prognosis in breast cancer patients, highlighting the clinical relevance of our findings. Importantly, KAT2B knockout mice are viable, raising the exciting prospect of targeting this dependency therapeutically. Taken together, we uncovered a crucial role of the NELF-E-KAT2B epigenetic axis in breast cancer carcinogenesis.
2023-01-28 | PXD031304 | JPOST Repository
Project description:Metabolic reprogramming is a hallmark of cancer. Herein we discover that the key glycolytic enzyme pyruvate kinase M2 isoform (PKM2), but not the related isoform PKM1, is methylated by co-activator-associated arginine methyltransferase 1 (CARM1). PKM2 methylation reversibly shifts the balance of metabolism from oxidative phosphorylation to aerobic glycolysis in breast cancer cells. Oxidative phosphorylation depends on mitochondrial calcium concentration, which becomes critical for cancer cell survival when PKM2 methylation is blocked. By interacting with and suppressing the expression of inositol-1,4,5-trisphosphate receptors (InsP3Rs), methylated PKM2 inhibits the influx of calcium from the endoplasmic reticulum to mitochondria. Inhibiting PKM2 methylation with a competitive peptide delivered by nanoparticles perturbs the metabolic energy balance in cancer cells, leading to a decrease in cell proliferation, migration and metastasis. Collectively, the CARM1-PKM2 axis serves as a metabolic reprogramming mechanism in tumorigenesis, and inhibiting PKM2 methylation generates metabolic vulnerability to InsP3R-dependent mitochondrial functions.
2021-07-30 | MTBLS533 | MetaboLights
Project description:Bone is the primary site of breast cancer metastasis and complications associated with bone metastases can lead to a significantly decreased quality of life in these patients. Thus, it is essential to gain a better understanding of the molecular mechanisms that underlie the emergence and growth of breast cancer skeletal metastases. Methods: To search for novel molecular mediators that influence breast cancer bone metastasis, we generated gene expression profiles from laser capture micro-dissected trephine biopsies of both breast cancer bone metastases and primary breast tumors that metastasized to bone. Bioinformatics analysis identified genes that are differentially expressed in breast cancer bone metastases compared to primary mammary tumors. Results: ABCC5, an ATP-dependent transporter, was found to be overexpressed in breast cancer osseous metastases relative to primary mammary tumors. In addition, ABCC5 was significantly up-regulated in human and mouse breast cancer cell lines with high bone-metastatic potential. Stable knockdown of ABCC5 significant reduced bone metastatic burden and osteolytic bone destruction in mice. The decrease in osteolysis was further associated with diminished osteoclast numbers. Conclusions: Our data, for the first time, suggests that ABCC5 functions as a mediator of breast cancer skeletal metastasis. ABCC5 expression in breast cancer cells is important for the efficient bone resorption mediated by osteoclasts. Hence, ABCC5 may be a potential therapeutic target for breast cancer bone metastasis. primary breast tumors vs. bone trephine biopsies
2012-11-09 | E-GEOD-39494 | biostudies-arrayexpress
Project description:Bone-marrow-derived mesenchymal stem cells promote breast cancer metastasis
| PRJNA102435 | ENA
Project description:Bone is the most common metastasis site in patients with breast cancer, and approximately up to 80% of patients with advanced breast cancer (BC) develop bone metastasis (BM), which leads to a worse prognosis with a median survival of 16 months and skeletal-related events (SREs), including severe bone pain, pathological fracture, hypercalcemia and lethal complications. Using quantitative proteomics mass-spectrometry (MS) analysis of the secretome from patient-derived primary BC cells (PBCs) and bone-metastatic BC cells (BMBCs), we identified an unreported breast cancer (BC) cells–secreted microprotein, osteolysin, encoded by tropomyosin 3 pseudogene 9 (TPM3P9) and clinically associated with BC bone-tropism.
2024-07-05 | PXD053732 |
Project description:Bone is the primary site of breast cancer metastasis and complications associated with bone metastases can lead to a significantly decreased quality of life in these patients. Thus, it is essential to gain a better understanding of the molecular mechanisms that underlie the emergence and growth of breast cancer skeletal metastases. Methods: To search for novel molecular mediators that influence breast cancer bone metastasis, we generated gene expression profiles from laser capture micro-dissected trephine biopsies of both breast cancer bone metastases and primary breast tumors that metastasized to bone. Bioinformatics analysis identified genes that are differentially expressed in breast cancer bone metastases compared to primary mammary tumors. Results: ABCC5, an ATP-dependent transporter, was found to be overexpressed in breast cancer osseous metastases relative to primary mammary tumors. In addition, ABCC5 was significantly up-regulated in human and mouse breast cancer cell lines with high bone-metastatic potential. Stable knockdown of ABCC5 significant reduced bone metastatic burden and osteolytic bone destruction in mice. The decrease in osteolysis was further associated with diminished osteoclast numbers. Conclusions: Our data, for the first time, suggests that ABCC5 functions as a mediator of breast cancer skeletal metastasis. ABCC5 expression in breast cancer cells is important for the efficient bone resorption mediated by osteoclasts. Hence, ABCC5 may be a potential therapeutic target for breast cancer bone metastasis.
2012-11-09 | GSE39494 | GEO
Project description:HMGA2/TET1/HOXA9 pathway regulates breast cancer growth and metastasis.
| PRJNA187192 | ENA