Homo sapiens
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PROVIDER: PRJNA382560 | ENA |
REPOSITORIES: ENA
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Project description:Metabolic diseases, including type 2 diabetes and obesity are relevant negative prognostic factor in patients with breast cancer (BC). We have investigated the mechanisms through which elevated glucose levels affect tamoxifen sensitivity of estrogen receptor positive (ER+) BC cells. We found that MCF7 BC cell sensitivity to tamoxifen was 2-fold reduced in 25mM glucose (HG), a concentration mimicking hyperglycaemia, compared to 5.5 mM glucose (LG), resembling normal fasting glucose levels in humans. Shifting MCF7 cells from HG to LG ameliorated their responsiveness to tamoxifen. RNA-Sequencing revealed that glucose modified the transcriptome of MCF7 cells. In particular, cell cycle-related genes were affected by glucose. Combining gene specific knockdown and treatment with human recombinant proteins, we identified the Connective Tissue Growth Factor (CTGF) as glucose-induced factor able to reduce MCF7 cell sensitivity to tamoxifen. Moreover, we found that both CTGF expression levels and tamoxifen responsiveness were enhanced co-culturing MCF7 cells with human adipocytes through an Interleukin-8 (IL8)-mediated mechanism. Indeed, IL8 inhibition reduced CTGF levels and rescued tamoxifen sensitivity in MCF7 cells. Interestingly, CTGF immuno-detection in bioptic specimens obtained from women with ER+ BC correlated with distant metastases (P-value = 0.000), hormone therapy resistance (P-value = 0.000), reduced overall (P-value = 0.051) and disease free survival (P-value = 0.000). Thus, glucose affects tamoxifen responsiveness directly modulating CTGF in BC cells, and indirectly promoting the adipocytes’ release of IL8. Both CTGF and IL8 may represent potential targets in novel therapeutic strategies to increase tamoxifen sensitivity.
2017-07-01 | GSE97647 | GEO
Project description:Resistance to tamoxifen is a major challenge in the treatment of estrogen receptor positive breast cancer. Acquired resistance to drug involves multilayered genetic and epigenetic regulation . The oncogene EZH2 plays significant role in the development of resistance against tamoxifen, widely used in the treatment of breast cancer. Inhibition of EZH2 has proven to reverse the tamoxifen resistance breast cancer cells back to the sensitive state. The molecular mechanism through which EZH2 inhibition triggers its effects are not known.This study was conducted to understand the global change in proteome profile of tamoxifen resistant MCF-7 breast cancer cells as a result of effect of EZH2 knockdown. Label Free Quantitative proteomics revealed a large number of proteins altered in acquired tamoxifen resistant cells compared to the sensitive cells. A total of 286 proteins were identified with normalized RT for each m/z out of which 86 proteins were upregulated by more than 1.3 fold and 98 proteins were down regulated by more than 1.3 fold in MCF-7 tamoxifen resistant breast cancer cells in comparison to the sensitive breast cancer cells. Upon EZH2 knockdown in tamoxifen resistant cells, a total of 115 proteins were found to be altered with 20 proteins upregulated by more than 1.3 fold and 49 proteins down regulated by more than 1.3 fold. Among the top upregulated proteins were L-lactate dehydrogenase A chain, Alpha and Gamma-enolase, Calreticulin, heat shock protein HSP-90-beta, Alpha-actinin-4, Elongation factor 1-alpha, Vimentin, Protein S100A6, Putative protein FAM10A5, Heterogeneous nuclear ribonucleoprotein A1 and Keratin 1. In addition, 15 proteins were found to be down regulated in EZH2si transfected tamoxifen sensitive cells which otherwise were highlyup regulated in resistant cells in the presence of normal level of EZH2. This indicates a possible regulation of these molecules by EZH2 leading to loss of resistance. Our data unveils important molecular players downstream to EZH2 knockdown leading to regain of sensitivity to tamoxifen in acquired tamoxifen resistance.Thus, EZH2 seems to exert its effects through regulation of metabolism, epithelial to mesenchymal transition and protein synthesis & folding. Hence, targeting EZH2 or the molecules down the cascade might be helpful in reacquiring sensitivity to tamoxifen intamoxifen-resistant cells.
2019-09-30 | PXD012609 | Pride
Project description:Endocrine resistance in breast cancer is a major clinical problem with poorly understood mechanisms. Mass spectrometry-based proteomics of a clinically-relevant tamoxifen-resistant cell line model identified increased levels of minichromosome maintenance proteins (MCM), including MCM3, as central in cell cycle and DNA replication protein-protein interaction networks associated with tamoxifen resistance. Lowering MCM3 protein expression in tamoxifen-resistant cells restored tamoxifen sensitivity and altered phosphorylation of several cell cycle regulators, such as p53(Ser315, 33), CHK1(Ser317) and cdc25b(Ser323), suggesting that MCM3 activation of important cell cycle-associated proteins overcomes tamoxifen’s anti-proliferative effects. High MCM3 expression in primary tumor tissue from two independent cohorts of ER+ breast cancer patients receiving adjuvant tamoxifen mono-therapy was an independent prognostic marker significantly associated with a shorter recurrence-free survival.
2022-02-22 | PXD001087 | Pride
Project description:An altered consistency of tumor microenvironment facilitates the progression of the tumor towards metastasis. Here we combine data from secretome and proteome analysis using mass spectrometry with microarray data from mesenchymal transformed breast cancer cells (MCF-7-EMT) to elucidate the drivers of epithelial-mesenchymal transition (EMT) and cell invasion. Suppression of connective tissue growth factor (CTGF) reduced invasion in 2D and 3D invasion assays and expression of transforming growth factor-beta-induced protein ig-h3 (TGFBI), Zinc finger E-box-binding homeobox 1 (ZEB1) and lysyl oxidase (LOX), while the adhesion of cell-extracellular matrix (ECM) in mesenchymal transformed breast cancer cells is increased. In contrast, an enhanced expression of CTGF leads to an increased 3D invasion, expression of fibronectin 1 (FN1), secreted protein acidic and cysteine rich (SPARC) and CD44 and a reduced cell ECM adhesion (fig. 1). Gonadotropin-releasing hormone (GnRH) agonist Triptorelin reduces CTGF expression in a Ras homolog family member A (RhoA)-dependent manner. Our results suggest that CTGF drives breast cancer cell invasion in vitro and therefore could be an attractive therapeutic target for drug development to prevent the spread of breast cancer.
2020-10-22 | PXD021539 | Pride
Project description:Tamoxifen resistance has been a major clinical problem and is accountable for relapse in about one third of ER positive breast cancer patients. Most of the recurrent patients will eventually receive chemotherapy. However, the chemosensitivity of these tamoxifen-resistant breast cancer patients has never been explored. In this study, we demonstrate that tamoxifen-resistant breast cancer cells express significantly more BARD1 and BRCA1, which results in the resistance to DNA-damaging chemotherapy including cisplatin and adriamycin , but not to paclitaxel. Silencing BARD1 or BRCA1 expression or inhibition of BRCA1 phosphorylation by Dinaciclib restored the sensitivity to cisplatin in tamoxifen-resistant cells. In addition, we identified that activated PI3K/AKT pathway in tamoxifen-resistant cells was responsible for the upregulation of BARD1 and BRCA1. PI3K inhibitors, BKM120 and BYL719, decreased the expression of BARD1 and BRCA1 in tamoxifen-resistant cells and re-sensitized them to cisplatin both in vitro and in xenografted mice. Higher BARD1 and BRCA1 expression was associated with poor prognosis of early breast cancer patients, especially the ones received radiotherapy, indicating the potential use of PI3K inhibitors to reverse chemoresistance and radioresistance in ER positive breast cancer patients.
2021-03-15 | GSE111926 | GEO
Project description:Tamoxifen, an antagonist to estrogen receptor (ER), is a first line drug used in breast cancer treatment. However, this therapy is complicated by the fact that a substantial number of patients exhibit either de novo or acquired resistance. To characterize the signaling mechanisms underlying the resistance to tamoxifen, we established a tamoxifen-resistant cell line by treating the MCF7 breast cancer cell line with tamoxifen for over 6 months. We showed that this cell line exhibited resistance to tamoxifen both in vitro and in vivo. In order to quantify the phosphorylation alterations associated with tamoxifen resistance, we performed SILAC-based quantitative phosphoproteomic profiling on the resistant and vehicle-treated sensitive cell lines where we identified >5,600 unique phosphopeptides. We found phosphorylation levels of 1,529 peptides were increased (>2 fold) and 409 peptides were decreased (<0.5-fold) in tamoxifen resistant cells compared to tamoxifen sensitive cells. Gene set enrichment analysis revealed that focal adhesion pathway was the top enriched signaling pathway activated in tamoxifen resistant cells. We observed hyperphosphorylation of the focal adhesion kinases FAK1 and FAK2 in the tamoxifen resistant cells. Of note, FAK2 was not only hyperphosphorylated but also transcriptionally upregulated in tamoxifen resistant cells. Suppression of FAK2 by specific siRNA knockdown could sensitize the resistant cells to the treatment of tamoxifen. We further showed that inhibiting FAK activity using the small molecule inhibitor PF562271 repressed cellular proliferation in vitro and tumor formation in vivo. More importantly, our survival analysis revealed that high expression of FAK2 significantly associated with short metastasis-free survival of ER-positive breast cancer patients treated with tamoxifen-based hormone therapy. Our studies suggest that FAK2 is a great potential target for the development of therapy for the treatment of hormone refractory breast cancers.
2016-05-25 | PXD001812 | Pride
Project description:Gene Expression Preferentially Regulated by Tamoxifen in Breast Cancer Cells
| PRJNA95129 | ENA
Project description:Cold atmospheric plasma reprograms the drug sensitivity of Tamoxifen-resistant MCF-7 breast cancer cell
| PRJNA376413 | ENA
Project description:Genome-wide analyses of the transcriptomes and transcription factor recruitment in estrogen receptor breast cancer cells in response to estradiol, IL1b, or TNFa treatments. Also, the role of inflammatory cytokines on affecting tamoxifen sensitivity is analyzed on a genome-wide scale.
2017-02-20 | GSE67295 | GEO
Project description:In this study, we probed the importance of OGT activity for the survival of Tamoxifen-sensitive (TamS) and Tamoxifen-resistant (TamR) breast cancer cells. Tamoxifen is an antagonist of estrogen receptor (ERα), a transcription factor expressed in over half of all breast cancers, and the defining characteristic of the ERα-positive disease. ERα-positive breast cancers are successfully treated with Tamoxifen; however, a significant number of patients develops Tamoxifen-resistant disease. We show here that in vitro development of Tamoxifen-resistance results in acquired sensitivity to OGT small molecule inhibitor OSMI-1. Global transcriptome profiling revealed that TamS cells adapt to OSMI-1 treatment by undergoing significant chromatin compaction. In the TamR cells, however, OGT inhibition induces ERRFI1 tumor-suppressor gene expression. ERRFI1 is an endogenous inhibitor of ERBB-signaling, while activation of the ERBB-signaling is one of the best understood mechanism for Tamoxifen-resistance. We show that ERRFI1 is selectively downregulated in ERα-positive breast cancers and breast cancers driven by ERBB2, and provide data to support that this occurs through promoter methylation. Finally, we show that increased ERRFI1 expression is associated with extended survival in patients with ERα-positive tumors (p=9.2e-8). In summary, we show that Tamoxifen-resistance is associated with acquired sensitivity to OSMI-1, and propose that this is explained in part through an epigenetic activation of the tumor-suppressor ERRFI1 in response to OSMI-1 treatment.
2020-10-22 | GSE148186 | GEO