Gene expression profiling of invasive breast cancer events from the tamoxifen prevention trial
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE12665 | GEO | 2011/12/08
SECONDARY ACCESSION(S): PRJNA112733
REPOSITORIES: GEO
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Project description:Gene expression profiling of invasive breast cancer events from the tamoxifen prevention trial validates low estrogen receptor mRNA level as the main determinant of tamoxifen resistance in estrogen receptor positive breast cancer. In NSABP Breast Cancer Prevention Trial (BCPT), tamoxifen reduced the incidence of estrogen receptor (ER) positive tumors but not estrogen receptor negative breast cancer. More importantly, only 69% of estrogen receptor positive tumors were prevented by tamoxifen. The ER positive tumors arising in tamoxifen arm provides an ideal clinical model for acquired tamoxifen resistance. Based on data from NSABP trial B14 which showed linear prediction of the degree of benefit from adjuvant tamoxifen by the levels of ESR1 mRNA coding for ER-alpha, we hypothesized a priori that level of ESR1 mRNA would be lower in ER positive tumors arising in tamoxifen arm compared to those in placebo arm of BCPT. Keywords: Gene expression profiling analysis Formalin fixed paraffin embedded tumor blocks with enough tumor tissue for RNA extraction were available from 108 cases (69 from placebo arm and 39 from tamoxifen arm) of the 264 that experienced invasive breast cancer (175 in placebo arm and 89 in tamoxifen arm) in BCPT before unblindings . Central ER immunohistochemistry identified 84 of them as ER positive (57 from placebo arm and 27 from tamoxifen arm). A novel protocol was developed and used to obtain microarray gene expression profiling from the degraded or fragmented RNA extracted from formalin fixed paraffin blocks.Hybridization intensity data were compiled using Partek Genomic Suite. After quantile normalization, genes with mean intensity below 500 were filtred out, which left 7743 probes with informative data. Data were log2 transformed for statistical analysis.
2011-12-08 | E-GEOD-12665 | biostudies-arrayexpress
Project description:Estrogen and estrogen receptor (ER) signaling play critical roles in the development of ER-positive breast cancer, and endocrine therapy is the frontline treatment for ER-positive breast cancer patients. However, the primary and acquired resistance to endocrine therapy including tamoxifen and fulvestrant remains as the major challenge in the clinic. Here, we identified an estrogen-induced lncRNA, LINC02568, through transcriptomic analysis, which is highly expressed in ER-positive breast cancer. LINC02568 is functional important in ER-positive breast cancer cell growth in vitro and tumorigenesis in vivo as well as endocrine therapy resistance. Mechanically, we demonstrated that LINC02568 regulates, in trans, estrogen/ERα-induced gene transcriptional activation by sponging miR-1233-5p to stabilize ESR1 mRNA in the cytoplasm. Meanwhile, LINC02568 contributes to tumor-specific pH homeostasis in breast cancer cells by regulating CA12 in cis in the nucleus. The dual functions of LINC02568 together contribute to breast cancer cell growth and tumorigenesis as well as endocrine therapy resistance. Antisense oligonucleotides (ASO) targeting LINC02568 significantly inhibits ER-positive breast cancer cell growth in vitro and tumorigenesis in vivo as well as resensitize tamoxifen-resistant cells to tamoxifen. Furthermore, combination treatment with ASO targeting LINC02568 and tamoxifen exhibits synergistic effect on tumor growth. Taken together, our findings revealed dual mechanisms of LINC02568 in regulating ERα signaling and pH homeostasis in ER-positive breast cancer, and indicated that targeting LINC02568 might represent a potential therapeutic avenue in clinic.
2023-09-13 | GSE217190 | GEO
Project description:The estrogen receptor (ER) is a well-established target for the treatment of breast cancer, with the majority of patients presenting as ER-positive (ER+). Endocrine therapy is a mainstay of breast cancer treatment but the development of resistance mutations in response to aromatase inhibitors, poor pharmacokinetic properties of fulvestrant, agonist activity of tamoxifen, and limited benefit for elacestrant leave unmet needs for patients with or without resistance mutations in ESR1, the gene that encodes the ER protein. Here we describe OP-1250, a novel, orally bioavailable complete ER antagonist and selective ER degrader. OP-1250, like fulvestrant, has no agonist activity on the ER and completely blocks estrogen-induced transcriptional activity. In addition, OP-1250 demonstrates favorable biochemical binding affinity, ER degradation, and antiproliferative activity in ER+ breast cancer models that is comparable or superior to other agents of interest. OP-1250 has superior pharmacokinetic properties relative to fulvestrant, including oral bioavailability and brain penetrance, as well as superior performance in wild-type and ESR1-mutant breast cancer xenograft studies. OP-1250 combines well with cyclin-dependent kinase 4 and 6 inhibitors in xenograft studies of ER+ breast cancer models and effectively shrinks intracranially implanted tumors, resulting in prolonged animal survival. With demonstrated preclinical efficacy exceeding fulvestrant in wild-type models, elacestrant in ESR1-mutant models, and tamoxifen in intracranial xenografts, OP-1250 has the potential to benefit patients with ER+ breast cancer.
2023-09-01 | GSE241764 | GEO
Project description:The estrogen receptor (ER) is a well-established target for the treatment of breast cancer, with the majority of patients presenting as ER-positive (ER+). Endocrine therapy is a mainstay of breast cancer treatment but the development of resistance mutations in response to aromatase inhibitors, poor pharmacokinetic properties of fulvestrant, agonist activity of tamoxifen, and limited benefit for elacestrant leave unmet needs for patients with or without resistance mutations in ESR1, the gene that encodes the ER protein. Here we describe OP-1250, a novel, orally bioavailable complete ER antagonist and selective ER degrader. OP-1250, like fulvestrant, has no agonist activity on the ER and completely blocks estrogen-induced transcriptional activity. In addition, OP-1250 demonstrates favorable biochemical binding affinity, ER degradation, and antiproliferative activity in ER+ breast cancer models that is comparable or superior to other agents of interest. OP-1250 has superior pharmacokinetic properties relative to fulvestrant, including oral bioavailability and brain penetrance, as well as superior performance in wild-type and ESR1-mutant breast cancer xenograft studies. OP-1250 combines well with cyclin-dependent kinase 4 and 6 inhibitors in xenograft studies of ER+ breast cancer models and effectively shrinks intracranially implanted tumors, resulting in prolonged animal survival. With demonstrated preclinical efficacy exceeding fulvestrant in wild-type models, elacestrant in ESR1-mutant models, and tamoxifen in intracranial xenografts, OP-1250 has the potential to benefit patients with ER+ breast cancer.
2023-09-01 | GSE241943 | GEO
Project description:The estrogen receptor (ER) is a well-established target for the treatment of breast cancer, with the majority of patients presenting as ER-positive (ER+). Endocrine therapy is a mainstay of breast cancer treatment but the development of resistance mutations in response to aromatase inhibitors, poor pharmacokinetic properties of fulvestrant, agonist activity of tamoxifen, and limited benefit for elacestrant leave unmet needs for patients with or without resistance mutations in ESR1, the gene that encodes the ER protein. Here we describe OP-1250, a novel, orally bioavailable complete ER antagonist and selective ER degrader. OP-1250, like fulvestrant, has no agonist activity on the ER and completely blocks estrogen-induced transcriptional activity. In addition, OP-1250 demonstrates favorable biochemical binding affinity, ER degradation, and antiproliferative activity in ER+ breast cancer models that is comparable or superior to other agents of interest. OP-1250 has superior pharmacokinetic properties relative to fulvestrant, including oral bioavailability and brain penetrance, as well as superior performance in wild-type and ESR1-mutant breast cancer xenograft studies. OP-1250 combines well with cyclin-dependent kinase 4 and 6 inhibitors in xenograft studies of ER+ breast cancer models and effectively shrinks intracranially implanted tumors, resulting in prolonged animal survival. With demonstrated preclinical efficacy exceeding fulvestrant in wild-type models, elacestrant in ESR1-mutant models, and tamoxifen in intracranial xenografts, OP-1250 has the potential to benefit patients with ER+ breast cancer.
2023-09-01 | GSE241942 | GEO
Project description:RNA sequencing (RNA-seq) detects estrogen receptor alpha gene (ESR1) fusion transcripts in estrogen receptor positive (ER+) breast cancer but their role in disease pathogenesis remains unclear. We performed sequencing on RNA extracted from metastatic biopsy samples from patients with ER+ breast cancer to assess the presence of fusion transcripts.
2021-11-23 | GSE189389 | GEO
Project description:Expression of estrogen receptor (ESR1) determines whether a breast cancer patient receives endocrine therapy as part of their adjuvant care, but does not guarantee patient response. However, the molecular factors that define endocrine response in ESR1-positive breast cancer patients remain poorly understood. Here, we characterize the DNA methylome of endocrine sensitivity and demonstrate the potential impact of differential DNA methylation on endocrine response in breast cancer. We show that DNA hypermethylation occurs predominantly at estrogen-responsive enhancers and is associated with reduced ESR1 binding and decreased gene expression of key regulators of ESR1-activity; thus providing a novel mechanism by which endocrine response is abated in ESR1-positive breast cancers. Conversely, we delineate that ESR1-responsive enhancer hypomethylation is critical in transition from normal mammary epithelial cells to endocrine responsive ESR1-positive cancer. Cumulatively these novel insights highlight the potential of ESR1-responsive enhancer methylation to both predict ESR1-positive disease and stratify ESR1-positive breast cancer patients as responders to endocrine therapy. Methylation profiling with Illumina's HumanMethylation450K array was performed on ESR1-positive hormone sensitive MCF7 cells, and three different well characterised endocrine resistant MCF7-derived cell lines; tamoxifen-resistant (TAMR), fulvestrant-resistant (FASR) and estrogen deprivation resistant (MCF7X) cells. For each cell line two biological replicates were profiled bringing the number of samples to eight.
2015-07-01 | E-GEOD-69118 | biostudies-arrayexpress
Project description:Estrogen signaling in breast cancer cells relies on long-range chromatin interactions connecting distal regulatory elements bound by the estrogen receptor 1 (ESR1) to target gene promoters. This ensures stimulus and subtype-specific transcriptional responses. Expanding on the function of CTCF and the cohesin complex in breast cancer, we demonstrate that the chromatin-looping factor ZNF143 binds the promoter of most early-response estrogen target genes connected to distal regulatory elements in ESR1-positive breast cancer cells. Its chromatin occupancy is unaffected by estrogen stimulation, supporting a stable three-dimensional genomic architecture within the early response to estrogen. Its loss abrogates the estrogen-induced transcriptional response and growth of breast cancer cells. When taking into account CTCF, ZNF143 and cohesin complex subunits, we show that chromatin-looping factors are genetically altered in over 20% of ESR1-positive primary breast tumors. Furthermore, the overexpression of ZNF143, CTCF and RAD21, a cohesin complex subunit, in ESR1-positive breast tumors associates with a worse clinical outcome. Overall, our results suggest that ZNF143 is a new critical effector of the estrogen response and highlights the contribution of the chromatin looping machinery to ESR1-positive breast cancer development. Examination of genome-wide ZNF143 binding in MCF-7 cells
2016-08-09 | E-GEOD-76454 | biostudies-arrayexpress
Project description:Estrogen signaling in breast cancer cells relies on long-range chromatin interactions connecting distal regulatory elements bound by the estrogen receptor 1 (ESR1) to target gene promoters. This ensures stimulus and subtype-specific transcriptional responses. Expanding on the function of CTCF and the cohesin complex in breast cancer, we demonstrate that the chromatin-looping factor ZNF143 binds the promoter of most early-response estrogen target genes connected to distal regulatory elements in ESR1-positive breast cancer cells. Its chromatin occupancy is unaffected by estrogen stimulation, supporting a stable three-dimensional genomic architecture within the early response to estrogen. Its loss abrogates the estrogen-induced transcriptional response and growth of breast cancer cells. When taking into account CTCF, ZNF143 and cohesin complex subunits, we show that chromatin-looping factors are genetically altered in over 20% of ESR1-positive primary breast tumors. Furthermore, the overexpression of ZNF143, CTCF and RAD21, a cohesin complex subunit, in ESR1-positive breast tumors associates with a worse clinical outcome. Overall, our results suggest that ZNF143 is a new critical effector of the estrogen response and highlights the contribution of the chromatin looping machinery to ESR1-positive breast cancer development. mRNA profiles of MCF-7 cells (siCtl or siZNF143) under vehicle (EtOH) or E2 (10 uM 17-beta oestradiol) stimulation
2016-08-09 | E-GEOD-76453 | biostudies-arrayexpress
Project description:A specific form of endometrial cancer (EC) can develop in breast cancer patients previously treated with tamoxifen (ET), an antagonist of estrogen receptor (ER) α that inhibits proliferation of ER positive breast cancer. ET tumors have a different phenotype than endometrial tumors which typically develop de novo without previous exposure to tamoxifen (EN). Here we aimed to identify specific protein markers that could serve as specific molecular targets in either phenotype. A set of total 45 formalin-fixed paraffin-embedded (FFPE) endometrial tumor tissue and adjacent myometrial tissue samples were analyzed using LC-MS/MS in SWATH-MS mode. We found that calcyphosin (CAPS) levels were elevated in EN tumors compared to ET tumors. The higher CAPS level in EC tissue invading to myometrium support its relationship to EC aggressiveness. Further, stathmin (STMN1) levels were found significantly elevated in ET vs. EN tumors and significantly associated with patient survival. This finding connects elevated levels of this cell cycle regulating, proliferation-associated protein with tamoxifen exposure. In a summary, using SWATH-MS we show that CAPS and STMN1 should be recognized as clinicopathologically different EC markers of which STMN1 is specifically connected with a previous tamoxifen exposition.
2020-05-05 | PXD017217 | Pride