Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Modeling Luminal breast cancer heterogeneity: Combination therapy to suppress hormone receptor negative cells in Luminal disease

ABSTRACT: Many Luminal breast cancers are heterogeneous, containing substantial numbers of estrogen (ER-) and progesterone (PR-) receptor-negative cells among the ER+PR+ ones. Currently, the Basal-like ER-PR- Luminobasal subpopulation in Luminal disease is not targeted for treatment. To address the relationships between ER+PR+ and ER-PR- cells in Luminal cancers and tightly control their ratios, we have generated isogenic pure Luminal (pLUM) and pure Luminobasal (pLB) cells from the same parental Luminal human breast cancer cell line. We show that pLUM suppress proliferation of pLB cells in mixed-cell 3D colonies in vitro and in pLUM:pLB mixed-cell xenografts in mice. High-throughput screening of FDA-approved oncology drugs reveal pLB cells are sensitive to the EGFR inhibitors Gefitinib and Erlotinib. In mixed-cell 3D colonies and mixed-cell solid mouse tumors, combination therapy with the antiestrogen Fulvestrant and the EGFRi Gefitinib constitutes a robust treatment strategy. We propose that response to combination endocrine/EGFRi therapies in heterogeneous Luminal cancers will improve long-term survival in patients whose primary tumors have been preselected for the appropriate biomarkers.

ORGANISM(S): Homo sapiens

PROVIDER: GSE55350 | GEO | 2014/07/14

SECONDARY ACCESSION(S): PRJNA239373

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Dataset's files

Source:

			Action	DRS
		Other

Items per page:

1 - 1 of 1

Similar Datasets

Maintenance of Hormone Responsiveness in Luminal Breast Cancers by Suppression of Notch

Project description:Luminal breast cancers express estrogen (ER) and/or progesterone (PR) receptors and respond to hormone therapies. Basal-like “triple negative” (TN) cancers lack steroid receptors but are cytokeratin (CK) 5-positive and require chemotherapy. Here we show that over half of primary ER+PR+ breast cancers contain an ER–PR–CK5+ “luminobasal” subpopulation exceeding 1% of cells. Starting from ER+PR+ luminal cell lines, we generated novel lines with varying luminal to luminobasal-cell ratios and studied their molecular and biological properties. In luminal disease, luminobasal cells expand in response to antiestrogen or estrogen withdrawal therapies. The phenotype and gene signature of the hormone resistant cells matches that of clinical TN basal-like and claudin-low disease. Luminobasal-cell expansion in response to hormone therapies is regulated by Notch1 signaling and can be blocked by gamma-secretase inhibitors (GSI). Our data establish a previously unrecognized plasticity of ER+PR+ luminal breast cancers that, without genetic manipulation, mobilizes outgrowth of hormone-resistant basal-like disease in response to treatment. This undesirable outcome can be prevented by combining endocrine therapies with Notch inhibition. 24 array samples

2011-12-21 | E-GEOD-31870 | biostudies-arrayexpress

Maintenance of Hormone Responsiveness in Luminal Breast Cancers by Suppression of Notch

2011-12-21 | GSE31870 | GEO

Estrogen and progesterone receptor dynamics in patient-derived luminal breast cancer xenografts

Project description:Progesterone receptors (PR) are co-expressed in over half of estrogen receptor (ER) positive breast cancers and predict positive response to endocrine therapy. PR can directly and globally modify ER action to attenuate tumor growth. However, whether this suppression occurs solely through PR-ER interactions remains unknown. We assessed tumor growth in two highly ER and PR positive breast cancer patient-derived xenografts (PDX) and found that natural and synthetic progestins potently antagonize the mitogenic effects of estrogens. Here we probed the genome-wide mechanisms by which this occurs. Chronic progestin treatment reversed expression of up to half of estrogen up- and downregulated genes at the transcript level. However, fewer than a quarter of ER DNA binding events were altered by progesterone. The PR cistrome showed an interesting bimodal distribution. In the first group, more than half of PR binding sites were co-occupied by ER, with a propensity for both receptors to coordinately gain or lose binding in the presence of progesterone. In the second group, PR, but not ER, was associated with a large fraction of RNA polymerase III (Pol III)-transcribed tRNA genes regardless of hormone treatment. Furthermore, PR formed a physical association with the Pol III holoenzyme. Select tRNAs with colocalization of PR and POLR3A at their promoters were reduced in tumors grown with estrogen plus progestin compared to estrogen alone. These data uncover a mechanism in solid tumors by which PR modulates the bioavailability of translational molecules that are necessary for robust tumor growth, which could indirectly impede ER action.

2017-02-28 | GSE93944 | GEO

Expression profiling of circulating miRNAs in Luminal A breast cancer

Project description:Breast cancer is a common disease with distinct tumor subtypes which can be phenotypically characterized by estrogen receptor, progesterone receptor and HER2/neu receptor status. MiRNAs play regulatory roles in tumor initiation and progression. Altered miRNA expression has been demonstrated in a variety of cancer states to date presenting the potential for exploitation as cancer specific biomarkers. Blood presents an attractive medium biomarker discovery. This study investigated systemic miRNAs differentially expressed in Luminal A (ER+PR+HER2/neu-) breast cancer and their effectiveness as oncologic biomarkers in the clinical setting. Blood samples were prospectively collected from consenting patients with Luminal A breast cancer (n=10) and controls (n=10). RNA was extracted, reverse transcribed and subjected to microarray analysis (n=10 Luminal A; n=10 Control). Differentially expressed miRNAs were identified by artificial neural network (ANN) data-mining algorithms.

2013-04-24 | GSE46355 | GEO

Proteomic profiling of Breast cell lines exhibiting epithelial or mesenchymal morphology

Project description:We performed quantitative TMT-based proteomic analysis of eight human-derived breast cell lines growing in 2D. The dataset includes the total and phospho-proteomes of seven tumour cell lines: T47D (Epithelial, Luminal, ER+/PR+/HER2-), BT474 (Epithelial, Luminal, ER+/PR+/HER2+), SKBR3 (Epithelial, Luminal, ER-/PR-/HER2+), MDA-MB-468 (Epithelial, Basal A, ER-/PR-/HER2-), MDA-MB-231 (Mesenchymal, Basal B, ER-/PR-/HER2-), MDA-MB-231-LM2 (Mesenchymal, Basal B, ER-/PR-/HER2-, a highly metastatic subpopulation 4175 from MDA-MB-231), and SUM159 (Mesenchymal, Basal B, ER-/PR-/HER2-) and one non-tumour cell line: MCF10A (Epithelial, Basal B, ER-/PR-/HER2-). We achieved a depth of over 8,000 proteins and a total of over 20,000 phosphopeptides with MS2 acquisition covering a wide range of biological processes. These eight lines encompass a wide range of genetic subtypes and have diverse morphologies in either 2D (epithelial vs mesenchymal), and/or in 3D environments (Mass, Grape-like, Stellate, Round) (Neve RM, 2006) (Kenny PA, 2007). The study also explored the effects of TGF-β1 during 10 days on the non-tumorigenic MCF10A cells, and their posterior washout and recovery for 40 days. TGF-β1 is a cytokine known to induce epithelial-to-mesenchymal transition (EMT), a process associated with cancer progression (Xu J, 2009) (Nieto, 2016). The data can be analysed in isolation or in combination with other orthogonal datasets such as transcriptomes or image-based data (OMICS), for the purpose of predicting tumour outcome, identifying markers, drug response or mechanisms of resistance to therapeutics. These data can provide insights for therapeutic strategies and better understanding of the diverse molecular landscapes of breast cancer cells.

2024-09-16 | PXD047164 | Pride

Comprehensive proteome, phosphoproteome and kinome characterization of luminal A breast cancer

Project description:Cancer tissues and noncancerous adjacent tissues (NATs) with the luminal A subtype (ER- and PR-positive, HER2-negative) were obtained from paired IDC and ILC patients respectively. Label-free quantitative proteomics and phosphoproteomics methods were used to detect differential proteins and the phosphorylation status between 10 paired breast cancer and NATs. Then, the difference in protein expression and its phosphorylation between IDC and ILC subtypes were explored. Meanwhile, the activation of kinases and their substrates was also revealed by Kinase-Substrate Enrichment Analysis (KSEA).

2023-03-22 | MSV000091530 | MassIVE

Microarray expression profiling study of Runx1-null and wild type luminal mammary epithelial cells

2014-11-26 | GSE47375 | GEO

Microarray expression profiling study of Runx1-null and wild type luminal mammary epithelial cells

Project description:RUNX1 encodes a RUNX family transcription factor (TF) and was recently identified as a novel mutated gene in human luminal breast cancers. We found that Runx1 is expressed in all subpopulations of murine mammary epithelial cells (MECs) except the secretory alveolar luminal cells. Conditional knockout of Runx1 in MECs by MMTV-Cre led to a decrease in luminal MECs, largely due to a profound reduction in the estrogen receptor (ER)-positive mature luminal subpopulation, a phenotype that could be rescued by loss of either Trp53 or Rb1. Mechanistically RUNX1 represses Elf5, a master regulatory TF gene for alveolar cells, and activates Foxa1, a key mature luminal TF gene involved in the ER program. Collectively, our data identified a key regulator of the ER+ luminal lineage whose disruption may contribute to development of ER+ luminal breast cancer when under the background of either TP53 or RB1 loss. Thoracic and inguinal mammary glands from 3 MMTV-Cre;Runx1L/L;R26Y and 3 MMTV-Cre;Runx1+/+;R26Y adult virgin females were dissected out, minced and digested to single cell suspension. Runx1L is the floxed conditional knockout allele of Runx1. R26Y is a conditional YFP reporter that would be turned on upon Cre-mediated recombination. FACSaria machine was used to sort out the YFP-marked luminal epithelial cell population of each of these 6 mice. Total RNA was isolated with Qiagen RNeasy kit and subsequently amplified by Nugen V2 and applied to Affymetrix mouse genome 430 2.0 arrays.

2014-11-26 | E-GEOD-47375 | biostudies-arrayexpress

Progesterone receptor-B enhances estrogen responsiveness of breast cancer cells via scaffolding PELP1- and estrogen receptor-containing transcription complexes

Project description:Progesterone and estrogen are important drivers of breast cancer proliferation. Herein, we probed estrogen receptor-α (ER) and progesterone receptor (PR) cross-talk in breast cancer models. Stable expression of PR-B in PR-low/ER+ MCF7 cells increased cellular sensitivity to estradiol and insulin-like growth factor 1 (IGF1), as measured in growth assays performed in the absence of exogenous progestin; similar results were obtained in PR-null/ER+ T47D cells stably expressing PR-B. Genome-wide microarray analyses revealed that unliganded PR-B induced robust expression of a subset of estradiol-responsive ER target genes, including cathepsin-D (CTSD). Estradiol-treated MCF7 cells stably expressing PR-B exhibited enhanced ER Ser167 phosphorylation and recruitment of ER, PR and the proline-, glutamate- and leucine-rich protein 1 (PELP1) to an estrogen response element in the CTSD distal promoter; this complex co-immunoprecipitated with IGF1 receptor (IGFR1) in whole-cell lysates. Importantly, ER/PR/PELP1 complexes were also detected in human breast cancer samples. Inhibition of IGF1R or phosphoinositide 3-kinase blocked PR-B-dependent CTSD mRNA upregulation in response to estradiol. Similarly, inhibition of IGF1R or PR significantly reduced ER recruitment to the CTSD promoter. Stable knockdown of endogenous PR or onapristone treatment of multiple unmodified breast cancer cell lines blocked estradiol-mediated CTSD induction, inhibited growth in soft agar and partially restored tamoxifen sensitivity of resistant cells. Further, combination treatment of breast cancer cells with both onapristone and IGF1R tyrosine kinase inhibitor AEW541 was more effective than either agent alone. In summary, unliganded PR-B enhanced proliferative responses to estradiol and IGF1 via scaffolding of ER-α/PELP1/IGF1R-containing complexes. Our data provide a strong rationale for targeting PR in combination with ER and IGF1R in patients with luminal breast cancer.

2015-03-15 | GSE45643 | GEO

Estrogen-regulated genes predict survival in estrogen receptor and/or progesterone receptor-positive breast cancers

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

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data