Expression data from Estrogen Receptor alpha-positive Progesterone Receptor-positive Mammary Tumors in STAT1-/- Mice.
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ABSTRACT:
ORGANISM(S): Mus musculus
SUBMITTER: Szeman Chan
PROVIDER: E-GEOD-31942 | biostudies-arrayexpress |
REPOSITORIES: biostudies-arrayexpress
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Project description:Aged STAT1-/- female mice spontaneously develop ERa+ PR+ mammary tumors that exhibit strikingly similar hormone-sensitivity and -dependency as human ERa+ luminal breast cancers. We used microarray data to compare the genetic relationships between the STAT1-/- mammary tumors and human breast cancers.
2011-12-15 | GSE31942 | GEO
Project description:Conventional transgenic and knockout models do not allow selective introduction of oncogenic alterations into the progenitor population of mammary cells; thus, the role of progenitor cells in mammary tumorigenesis is yet unknown. By generating transgenic mice expressing tva – encoding the receptor for avian leukosis virus subgroup A (ALV/A) – from the Keratin 6a (K6) gene promoter, we found that K6+ mammary cells are bipotential progenitor cells, but not stem cells. These K6+ cells were readily induced to form tumors by intraductal injection of RCAS (an ALV/A-derived vector) carrying the gene encoding polyoma middle T antigen. Compared with tumors induced by the same oncogene-expressing virus in transgenic mice expressing tva from the commonly used MMTV LTR or other murine models of breast cancer, tumors in this K6-tva line were unique in that they resemble the normal breast-like subtype of human breast cancer. Consequently, these observations suggest that the cell of origin affects mammary tumor phenotypes. This K6-tva model may be useful for preclinical testing of targeted therapy for normal-like breast cancers in patients. Keywords: Three group comparison We carried out Affymetrix array analysis of five RCAS-PyMT-induced tumors each from K6-tva mice and MMTV-tva mice, as well as five mammary tumors from MMTV-PyMT transgenic mice.
2011-05-09 | E-GEOD-20614 | biostudies-arrayexpress
Project description:While protein arginine methyltransferases (PRMTs) and PRMT-catalyzed protein methylation have been well-known to be involved in a myriad of biological processes, their roles in carcinogenesis, particularly in estrogen receptor alpha (ERa)-positive breast cancers, remain incompletely understood. Here we focused on investigating PRMT4 (also called coactivator associated arginine methyltransferase 1, CARM1) due to its high expression and the associated poor prognosis in ERa-positive breast cancers. We first uncovered the chromatin-binding landscape and transcriptional targets of CARM1 in the presence of estrogen in ERa-positive breast cancer cells employing genomic and transcriptomics approaches. CARM1 was found to be predominantly and specifically recruited to ERa-bound active enhancers and essential for the transcriptional activation of cognate estrogen-induced gene transcriptional activation in response to estrogen. Global mapping of CARM1 substrates revealed that CARM1 methylates a large cohort of proteins with diverse biological functions, including regulation of intracellular estrogen receptor signaling, chromatin organization, chromatin remodeling and others. Intriguingly, a number of proteins were hypermethylated exclusively by CARM1 on a cluster of arginine residues. Exemplified by MED12, hypermethylation of these proteins by CARM1 served as a molecular beacon for recruiting coactivator protein, tudor domain-containing 3 (TDRD3), to ensure the full activation of estrogen/ERa target genes. In consistent with its critical role in estrogen-induced gene transcriptional activation, CARM1 was found to promote cell proliferation of ERa-positive breast cancer cells in vitro and tumor growth in mice. Taken together, our study uncovered a “hypermethylation” strategy utilized by CARM1 in gene transcriptional regulation, and suggested that CARM1 can server as a therapeutic target for breast cancer treatment.
2020-03-31 | GSE124448 | GEO
Project description:While protein arginine methyltransferases (PRMTs) and PRMT-catalyzed protein methylation have been well-known to be involved in a myriad of biological processes, their roles in carcinogenesis, particularly in estrogen receptor alpha (ERa)-positive breast cancers, remain incompletely understood. Here we focused on investigating PRMT4 (also called coactivator associated arginine methyltransferase 1, CARM1) due to its high expression and the associated poor prognosis in ERa-positive breast cancers. We first uncovered the chromatin-binding landscape and transcriptional targets of CARM1 in the presence of estrogen in ERa-positive breast cancer cells employing genomic and transcriptomics approaches. CARM1 was found to be predominantly and specifically recruited to ERa-bound active enhancers and essential for the transcriptional activation of cognate estrogen-induced gene transcriptional activation in response to estrogen. Global mapping of CARM1 substrates revealed that CARM1 methylates a large cohort of proteins with diverse biological functions, including regulation of intracellular estrogen receptor signaling, chromatin organization, chromatin remodeling and others. Intriguingly, a number of proteins were hypermethylated exclusively by CARM1 on a cluster of arginine residues. Exemplified by MED12, hypermethylation of these proteins by CARM1 served as a molecular beacon for recruiting coactivator protein, tudor domain-containing 3 (TDRD3), to ensure the full activation of estrogen/ERa target genes. In consistent with its critical role in estrogen-induced gene transcriptional activation, CARM1 was found to promote cell proliferation of ERa-positive breast cancer cells in vitro and tumor growth in mice. Taken together, our study uncovered a “hypermethylation” strategy utilized by CARM1 in gene transcriptional regulation, and suggested that CARM1 can server as a therapeutic target for breast cancer treatment.
2020-01-17 | GSE124447 | GEO
Project description:Estrogen Receptor alpha (ERa) is the main driver of luminal breast cancer development and progression, and represents the main drug target in patient care. ERa chromatin binding has been extensively studied in breast cancer cell lines and a number of human tumors, often focused on differential binding patterns between groups or conditions. However, little is known about the inter-tumor heterogeneity of ERa chromatin action. Here, we use a large set of ERa ChIP-seq data from 70 ERa+ breast cancers (40 women and 30 men) to explore general inter-patient heterogeneity in ERa DNA binding in breast cancers. We found a total universe of 84,565 and 101,653 ERa sites in females and males respectively, with merely 1.2% and 5% of sites shared in at least half of the tumors analyzed, reflecting a high level of inter-patient heterogeneity. This heterogeneity was found to be most variable at putative enhancers as opposed to promoter regions, potentially reflecting a level of functional redundancy in enhancer action. Interestingly, commonly shared ERa sites showed the highest estrogen-driven enhancer activity, as determined using a massive parallel reporter assay, and were most-engaged in long-range chromatin interactions. In addition, the most-commonly shared ERa-occupied enhancers were found enriched for breast cancer risk SNP loci. We experimentally illustrate such SNVs can impact chromatin binding potential for ER and its pioneer factor FOXA1. Finally, in the TCGA breast cancer cohort, we could confirm these variations to associate with differences in expression for the target gene. Cumulatively, our data reveal a natural hierarchy of ERa-chromatin interactions in breast cancers within a highly heterogeneous inter-tumor ERa landscape, with the most-common shared regions being most active and affected by germline functional risk SNPs for breast cancer development.
2024-03-27 | GSE244844 | GEO
Project description:Estrogen Receptor alpha (ERa) is the main driver of luminal breast cancer development and progression, and represents the main drug target in patient care. ERa chromatin binding has been extensively studied in breast cancer cell lines and a number of human tumors, often focused on differential binding patterns between groups or conditions. However, little is known about the inter-tumor heterogeneity of ERa chromatin action. Here, we use a large set of ERa ChIP-seq data from 70 ERa+ breast cancers (40 women and 30 men) to explore general inter-patient heterogeneity in ERa DNA binding in breast cancers. We found a total universe of 84,565 and 101,653 ERa sites in females and males respectively, with merely 1.2% and 5% of sites shared in at least half of the tumors analyzed, reflecting a high level of inter-patient heterogeneity. This heterogeneity was found to be most variable at putative enhancers as opposed to promoter regions, potentially reflecting a level of functional redundancy in enhancer action. Interestingly, commonly shared ERa sites showed the highest estrogen-driven enhancer activity, as determined using a massive parallel reporter assay, and were most-engaged in long-range chromatin interactions. In addition, the most-commonly shared ERa-occupied enhancers were found enriched for breast cancer risk SNP loci. We experimentally illustrate such SNVs can impact chromatin binding potential for ER and its pioneer factor FOXA1. Finally, in the TCGA breast cancer cohort, we could confirm these variations to associate with differences in expression for the target gene. Cumulatively, our data reveal a natural hierarchy of ERa-chromatin interactions in breast cancers within a highly heterogeneous inter-tumor ERa landscape, with the most-common shared regions being most active and affected by germline functional risk SNPs for breast cancer development.
2024-03-27 | GSE244840 | GEO
Project description:The estrogen receptor alpha (ERa) drives the growth of two-thirds of all breast cancers. Endocrine therapy impinges on estrogen-induced ERa activation to block tumor growth. However, half of ERa-positive breast cancers are tolerant or acquire endocrine therapy resistance. Here we demonstrate that breast cancer cells undergo genome-wide reprogramming of their chromatin landscape, defined by epigenomic maps and chromatin openness, as they acquire resistance to endocrine therapy. This reveals a role for the Notch pathway while excluding classical ERa signaling. In agreement, blocking Notch signaling, using gamma-secretase inhibitors, or targeting its downstream gene PBX1 abrogates growth of endocrine therapy-resistant breast cancer cells. Moreover Notch signaling through PBX1 directs a transcriptional program predictive of tumor outcome and endocrine therapy response.
2013-05-01 | GSE37323 | GEO
Project description:Molecular subtypes of breast cancer are characterized by patterns of gene expression, which can be used to predict response to therapy and overall clinical outcome. The luminal breast cancer subtypes are defined by the expression of ER-alpha (ERa) and a set of ERa-associated genes. The transcription factor activator protein 2C (TFAP2C, AP-2C, AP-2g) transcription factor plays a critical role in regulating cell growth and differentiation during ectodermal development and has been implicated in the regulation of ERa and other luminal-associated genes in breast cancer. While TFAP2C has been established as a prognostic factor in human breast cancer, the role of TFAP2C in development of the luminal epithelial cells in the normal mammary gland and in breast cancer have remained elusive. Herein, we demonstrate a critical role of TFAP2C in maintaining the luminal differentiation phenotype during normal mammary development and in luminal breast carcinoma cell lines.
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Project description:The prognosis of a patient with Estrogen Receptor (ER) and/or Progesterone Receptor (PR)-positive breast cancer is highly variable. Therefore, we developed a gene-expression based outcome predictor for ER+ and/or PR+ (i.e. Luminal) breast cancer patients using biological properties of the tumors. First, we identified estrogen-regulated genes using the ER+ MCF-7 breast cancer cell line treated with estrogen. The estrogen-induced gene set was then used to hierarchically cluster a training set of 65 ER+ and/or PR+ tumors into 2 group, which showed survival differences (p=0.0004). Next, supervised analyses based upon these two groups was performed and identified 822 genes that optimally defined these two groups, with the poor prognosis Group IIE tumors showing a proliferation signature and high expression of anti-apoptosis genes and the good outcome Group IE showing the high expression of estrogen and GATA3-induced genes. Centroids were created for each group and applied to ER+ and/or PR+ tumors from three published datasets. For all datasets, Kaplan-Meier survival analyses showed a statistically significant difference in Relapse-Free Survival (and Overall) between Group IE and IIE tumors. Multivariate Cox analysis of the largest test dataset also showed that this predictor was adding independent information. This study provides new biological information concerning differences within Luminal/ER+ breast cancers and a means of predicting long term outcomes in ER+ and/or PR+ breast cancer patients. Keywords: other
2005-12-01 | GSE2740 | GEO
Project description:The estrogen receptor alpha (ERa) drives the growth of two-thirds of all breast cancers. Endocrine therapy impinges on estrogen-induced ERa activation to block tumor growth. However, half of ERa-positive breast cancers are tolerant or acquire endocrine therapy resistance. Here we demonstrate that breast cancer cells undergo genome-wide reprogramming of their chromatin landscape, defined by epigenomic maps and chromatin openness, as they acquire resistance to endocrine therapy. This reveals a role for the Notch pathway while excluding classical ERa signaling. In agreement, blocking Notch signaling, using gamma-secretase inhibitors, or targeting its downstream gene PBX1 abrogates growth of endocrine therapy-resistant breast cancer cells. Moreover Notch signaling through PBX1 directs a transcriptional program predictive of tumor outcome and endocrine therapy response. Comparing histone modifications (H3K4me2 and H3K36me3), chromatin openness (FAIRE) and PBX1 binding between endocrine therapy sensitive MCF7 and resistant MCF7-LTED cells.
2013-05-01 | E-GEOD-37323 | biostudies-arrayexpress