Homo sapiens
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ABSTRACT:
PROVIDER: PRJNA111897 | ENA |
REPOSITORIES: ENA
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Project description:Emergence of antiestrogen-resistant cells in MCF-7 cells during suppression of estrogen signaling is a widely accepted model of acquired breast cancer resistance to endocrine therapy. To obtain insight into the genomic basis of endocrine therapy resistance, we characterized MCF-7 monoclonal sublines that survived 21-day exposure to tamoxifen (T-series sublines) or fulvestrant (F-series sublines) and sublines unselected by drugs (U-series). All T/F-sublines were resistant to the cytocidal effects of both tamoxifen and fulvestrant. However, their responses to the cytostatic effects of fulvestrant varied greatly, and their remarkably diversified morphology showed no correlation with drug resistance. mRNA expression profiles of the U-sublines differed significantly from those of the T/F-sublines, whose transcriptomal responsiveness to fulvestrant was largely lost. A set of genes strongly expressed in the U-sublines successfully predicted metastasis-free survival of breast cancer patients. Most T/F-sublines shared highly homogeneous genomic DNA aberration patterns that were distinct from those of the U-sublines. Genomic DNA of the U-sublines harbored many aberrations that were not found in the T/F-sublines. These results suggest that the T/F-sublines are derived from a common monoclonal progenitor that lost transcriptomal responsiveness to antiestrogens as a consequence of genetic abnormalities many population doublings ago, not from the antiestrogen-sensitive cells in the same culture during the exposure to antiestrogens. Thus, the apparent acquisition of antiestrogen resistance by MCF-7 cells reflects selection of preexisting drug-resistant subpopulations without involving changes in individual cells. Our results suggest the importance of clonal selection in endocrine therapy resistance of breast cancer.
2009-08-27 | GSE14986 | GEO
Project description:We previously identified small molecules that fit into a BRCA1-binding pocket within estrogen receptor-alpha (ER), mimic the ability of BRCA1 to inhibit ER activity (“BRCA1-mimetics”), and overcome antiestrogen resistance. One such compound, the hydrochloride salt of NSC35446 (“NSC35446.HCl”), also inhibited growth of antiestrogen-resistant LCC9 tumor xenografts. The purpose of this study was to investigate the down-stream effects of NSC35446.HCl and its mechanism of action. Methods: Here, we studied antiestrogen-resistant (LCC9, T47DCO, MCF-7/RR, LY2), ER-negative (MDA-MB-231, HCC1806, MDA-MB-468), and antiestrogen-sensitive (MCF-7) cell lines. Techniques utilized include RNA-seq, qRT-PCR, cell growth analysis, cell-cycle analysis, Western blotting, luciferase reporter assays, TUNEL assays, in-silico analysis of the IKKB gene, and ChIP assays. Results: NSC35446.HCl inhibited proliferation and induced apoptosis in antiestrogen resistant LCC9, T47DCO, MCF-7/RR, and LY2 cells but not in ER-negative breast cancer cell lines. IKKB (IKKβ, IKBKB), an upstream activator of NF-B, was identified as a BRCA1-mimetic-regulated gene, based on an RNA-seq analysis; and NSC35446.HCl inhibited IKKB mRNA and protein expression in LCC9 cells. NSC35446.HCl also inhibited NF-B activity and expression of NF-B target genes. In-silico analysis of the IKKB promoter identified nine estrogen response element (ERE) half-sites and one ERE-like full-site. ChIP assays revealed that ER was recruited to the ERE-like full-site and five of the nine half-sites and that ER recruitment was inhibited by NSC35446.HCl in LCC9 and T47DCO cells. Conclusions: These studies identify functional EREs in the IKKB promoter and identify IKKB as an NSC35446.HCl-regulated gene; and they suggest that NF-B and IKKB, which were previously linked to antiestrogen resistance, are targets for NSC35446.HCl in reversing antiestrogen resistance.
2017-07-21 | GSE101691 | GEO
Project description:genome-wide expression profiling of MCF-7, MCF-7/TamR and CAP-treated MCF-7/TamR cell. In result, cold atmospheric plasma re-sensitizes the Tamoxifen-resistant MCF-7 (MCF-7/TamR) breast cancer cell to the drug.
2017-07-12 | GSE95208 | GEO
Project description:Purpose: Investigation of clonal heterogeneity may be key to understanding mechanisms of therapeutic failure in human cancer. However, little is known on the consequences of therapeutic intervention on the clonal composition of solid tumors. Experimental Design: Here, we used 33 single cell–derived subclones generated from five clinical glioblastoma specimens for exploring intra- and interindividual spectra of drug resistance profiles in vitro. In a personalized setting, we explored whether differences in pharmacologic sensitivity among subclones could be employed to predict drug-dependent changes to the clonal composition of tumors. Results: Subclones from individual tumors exhibited a remarkable heterogeneity of drug resistance to a library of potential antiglioblastoma compounds. A more comprehensive intratumoral analysis revealed that stable genetic and phenotypic characteristics of coexisting subclones could be correlated with distinct drug sensitivity profiles. The data obtained from differential drug response analysis could be employed to predict clonal population shifts within the naïve parental tumor in vitro and in orthotopic xenografts. Furthermore, the value of pharmacologic profiles could be shown for establishing rational strategies for individualized secondary lines of treatment. Conclusions: Our data provide a previously unrecognized strategy for revealing functional consequences of intratumor heterogeneity by enabling predictive modeling of treatment-related subclone dynamics in human glioblastoma
2016-12-19 | GSE72927 | GEO
Project description:Purpose: Investigation of clonal heterogeneity may be key to understanding mechanisms of therapeutic failure in human cancer. However, little is known on the consequences of therapeutic intervention on the clonal composition of solid tumors. Experimental Design: Here, we used 33 single cell–derived subclones generated from five clinical glioblastoma specimens for exploring intra- and interindividual spectra of drug resistance profiles in vitro. In a personalized setting, we explored whether differences in pharmacologic sensitivity among subclones could be employed to predict drug-dependent changes to the clonal composition of tumors. Results: Subclones from individual tumors exhibited a remarkable heterogeneity of drug resistance to a library of potential antiglioblastoma compounds. A more comprehensive intratumoral analysis revealed that stable genetic and phenotypic characteristics of coexisting subclones could be correlated with distinct drug sensitivity profiles. The data obtained from differential drug response analysis could be employed to predict clonal population shifts within the naïve parental tumor in vitro and in orthotopic xenografts. Furthermore, the value of pharmacologic profiles could be shown for establishing rational strategies for individualized secondary lines of treatment. Conclusions: Our data provide a previously unrecognized strategy for revealing functional consequences of intratumor heterogeneity by enabling predictive modeling of treatment-related subclone dynamics in human glioblastoma
2016-12-19 | GSE72732 | GEO
Project description:Most triple negative breast cancers (TNBCs) are aggressively metastatic with a high degree of intratumoral heterogeneity. We employed patient-derived xenograft models established from the breast tumors of patients with treatment-naïve metastatic TNBC to study clonal dynamics during metastasis. Genomic sequencing coupled with high-complexity barcode-mediated clonal tracking revealed robust alterations in clonal architecture between primary tumors and corresponding metastases that were deterministic rather than stochastic. The presence of numerous rare subclones in each metastatic lesion demonstrated that polyclonal seeding occurred and that heterogeneous populations of low-abundance clones were maintained in metastases. An identical population of subclones was enriched in lung, liver, and brain metastases, demonstrating that primary tumor clones harbor properties enabling them to seed and thrive in multiple organ sites. Further, clones that dominated multi-organ metastases shared a genomic lineage. Thus, intrinsic properties of rare primary tumor subclones enable the seeding and colonization of metastases in multiple organ sites.
2018-12-11 | GSE120753 | GEO
Project description:Human breast cancer cell line MCF-7 is usually sensitive to chemotherapy drug BMS-554417, an insulin receptor (IR) and insulin-like growth factor receptor (IGFR) inhibitor. However, through step-wise increase in BMS-554417 doses in culture media, we were able able to screen and select a single MCF-7 clone that is BMS-554417 resistant. It is cross resistant to BMS-536924. This new line of MCF-7 cells was named as MCF-7R4. The transcriptome profiling of both MCF-7 and MCF-7R4 was performed using Affymetrix HG-U133 plus2.0 GeneChip arrays.
2009-11-06 | GSE18912 | GEO
Project description:Bortezomib is a proteasome inhibitor used in severel different hematological malignancies. Resistance to this drug is still poorly understood. In order get more insight in the resistance mechanism, we developed several bortezomib resistant subclones of the THP-1 monocytic/macrophage cell line. On these subclones expression arrays were performed. We performed expression array three different bortezomib resistant subclones of the THP-1 cell line. The resistant subclones were spotted against the parental THP-1 wildtype cell line.
2008-06-14 | E-GEOD-11771 | biostudies-arrayexpress
Project description:Microparticles (MPs) comprise the major source of systemic RNA including microRNA (miRNA), the aberrant expression of which appears to be associated with stage, progression and spread of many cancers. We have shown MPs to transfer multidrug resistance proteins accross both haematological and and non-haematological cancers. using microarray miRNA profiling analysis we now analyze changes in miRNA profiles of both cancer types following microparticle transfer. We identified certain upregulated miRNAs in both cancer types. Total RNA was extracted and pooled from duplicate experiments for hybridization on Affymetrix microarrays from (i) the parental drug sensitive leukaemia (CEM) or breast cancer (MCF-7) cells, (ii) their Multidrug Resistant strains leukaemia (VLB100) or breast cancer ( DX cells), (iii) the microparticles isolated from the resistant cells: VLBMP or DXMP, and (iv) the cocultured samples: sensitive cell co-incubated with MPs from their resistant cells ( leukaemia: CEM+VLBMP) or(breast cancer: MCF-7+DXMP). We sought to examine the miRNA profiles of the drug sensitve cells after MP transfer from drug resistant cells across leukaemia nd breact cancer cell lines.
2012-06-08 | E-GEOD-34560 | biostudies-arrayexpress
Project description:Human breast cancer cell line MCF-7 is usually sensitive to chemotherapy drug BMS-554417, an insulin receptor (IR) and insulin-like growth factor receptor (IGFR) inhibitor. However, through step-wise increase in BMS-554417 doses in culture media, we were able able to screen and select a single MCF-7 clone that is BMS-554417 resistant. It is cross resistant to BMS-536924. This new line of MCF-7 cells was named as MCF-7R4. The transcriptome profiling of both MCF-7 and MCF-7R4 was performed using Affymetrix HG-U133 plus2.0 GeneChip arrays. Five replicates of MCF-7 and five replicates of MCF-7R4 were profiled.
2009-11-05 | E-GEOD-18912 | biostudies-arrayexpress