Phosphatome profiling of estrogen receptor negative breast cancer
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
SUBMITTER: Ramon Manzano
PROVIDER: E-GEOD-51999 | biostudies-arrayexpress |
REPOSITORIES: biostudies-arrayexpress
Similar Datasets
Project description:Purpose: To characterize the expression of phosphatases in estrogen receptor negative breast cancer Little is known about the role of phosphatases in the major estrogen receptor negative breast cancer phenotypes (i.e. those overexpressing ERBB2 and the triple negative). We carried out microarray phosphatome profiling in 41 estrogen receptor negative (ER-) breast cancer patients (as determined by immunohistochemistry (IHC)) containing both ERBB2+ and ERBB2- in order to characterize the differences between these groups by Statistical Analysis of Microarrays (SAM). Our findings point to the importance of the MAPK and PI3K pathways in ER- BCs as some of the most differentially expressed phosphatases (like DUSP4 and DUSP6) share ERK as substrate, or regulate the PI3K pathway (INPP4B, PTEN). These observations are also confirmed by pathway and GSEA analysis. It is shown that both ER- ERBB2+ and triple negative breast cancers have a distinctive pattern of phosphatase RNA expression.
2014-06-30 | GSE51999 | GEO
Project description:Cross talk between the Estrogen Receptor (ER) and ErbB2/HER-2 pathways have long been implicated in breast cancer aetiology and drug response1, yet no direct connection at a transcriptional level has been shown. We now show that estrogen-ER and tamoxifen-ER complexes directly repress ErbB2 transcription via a cis-regulatory element within the ERBB2 gene. We implicate the Paired Box 2 gene product (Pax2), in a novel role, as a crucial mediator of ER repression of ErbB2 by the anti-cancer drug tamoxifen. We show that Pax2 and the ER co-activator AIB-1/SRC-3 compete for binding and regulation of ErbB2 transcription, the outcome of which determines tamoxifen response in breast cancer cells. The repression of ErbB2 by ER-Pax2 links these two important breast cancer subtypes and suggests that aggressive ErbB2 positive tumours can originate from ER positive luminal tumours by circumventing this repressive mechanism. These data provide mechanistic insight into the molecular basis of endocrine resistance in breast cancer.
2008-09-27 | E-TABM-563 | biostudies-arrayexpress
Project description:Phosphoinositide-3-kinase/protein-kinaseB/mammalian target of rapamycin (PI3K/AKT/mTOR) signalling plays an important role in breast cancer (BC). Its interaction with estrogen receptor (ER) signalling becomes more complex and inter-dependent with acquired endocrine resistance. Targeting mTOR combined with endocrine therapy has shown clinical utility, however, a negative feedback-loop exists downstream of PI3K/AKT/mTOR. Direct blockade of AKT together with endocrine therapy may improve BC treatment. AZD5363, a novel pan-AKT kinase catalytic inhibitor, was examined in a panel of ER+ BC cell lines (MCF7, HCC1428, T47D, ZR75.1) adapted to long-term-estrogen-deprivation (LTED) or tamoxifen (TamR). AZD5363 caused a dose-dependent decrease in proliferation in all cell lines tested (GI50<500nM) except HCC1428 and HCC1428-LTED. T47D-LTED and ZR75-LTED were the most sensitive of the lines (GI50~100nM). AZD5363 re-sensitised TamR cells to tamoxifen and acted synergistically with fulvestrant. AZD5363 decreased p-AKT/mTOR targets leading to a reduction in ERα-mediated transcription in a context specific manner and concomitant decrease in recruitment of ER and CREB-binding protein (CBP) to estrogen-response-elements located on the TFF1, PGR and GREB1 promoters. Furthermore, AZD5363 reduced expression of cell-cycle-regulatory proteins. Global gene expression highlighted ERBB2-ERBB3, ERK5 and IGF1 signaling pathways driven by MYC as potential feedback-loops. Combined treatment with AZD5363 and fulvestrant showed synergy in an ER+ patient derived xenograft and delayed tumour progression post-cessation of therapy. These data support the combination of AZD5363 with fulvestrant as a potential therapy for BC that is sensitive or resistant to E-deprivation or tamoxifen and that activated AKT is a determinant of response, supporting the need for clinical evaluation. Cell lines were treated in biological triplicates in the absence of estrogen with or without AZD5363 for 24hours in order to identify gene changes associated with perturbation of AKT signalling
2015-06-29 | E-GEOD-69893 | biostudies-arrayexpress
Project description:We aim to elucidate the mechanisms of how PI3K inhibition is promoting estrogen receptor (ER) activation and ER dependency in breast cancer.
2017-04-01 | GSE95366 | GEO
Project description:Activation of the PI3K pathway in estrogen receptor α (ER)-positive (+) breast cancer is associated with reduced ER expression and activity, luminal B subtype, and poor outcome. PTEN is a negative regulator of the PI3K pathway typically lost in ER-negative (-) breast cancer. To clarify the effect of PTEN down-regulation on the response of ER+/HER2- breast cancer to endocrine therapy, we established reduced PTEN cell models using inducible knockdown. We found that only moderate PTEN reduction is sufficient to enhance PI3K signaling, generate a gene signature associated with luminal B subtype, and cause endocrine resistance. Combining endocrine therapy with mTOR, AKT, or MEK inhibitors improves antitumor activity, but the efficacy varies by type of endocrine therapy and the specific inhibitor. Fulvestrant plus an AKT inhibitor is the most potent combination when PTEN is reduced, inducing apoptosis and tumor regression. This combination deserves further study in patients with PI3K pathway activation.
2014-06-30 | GSE53300 | GEO
Project description:Abstract BACKGROUND: The basal-like breast cancer (BLBC) subtype is characterized by positive staining for basal mammary epithelial cytokeratin markers, lack of hormone receptor and HER2 expression, and poor prognosis with currently no approved molecularly-targeted therapies. The oncogenic signaling pathways driving basal-like tumorigenesis are not fully elucidated. METHODS: One hundred sixteen unselected breast tumors were subjected to integrated analysis of phosphoinositide 3-kinase (PI3K) pathway related molecular aberrations by immunohistochemistry, mutation analysis, and gene expression profiling. Incidence and relationships between molecular biomarkers were characterized. Findings for select biomarkers were validated in an independent series. Synergistic cell killing in vitro and in vivo tumor therapy was investigated in breast cancer cell lines and mouse xenograft models, respectively. RESULTS: Sixty-four % of cases had an oncogenic alteration to PIK3CA, PTEN, or INPP4B; when including upstream kinases HER2 and EGFR, 75 % of cases had one or more aberration including 97 % of estrogen receptor (ER)-negative tumors. PTEN-loss was significantly associated to stathmin and EGFR overexpression, positivity for the BLBC markers cytokeratin 5/14, and the BLBC molecular subtype by gene expression profiling, informing a potential therapeutic combination targeting these pathways in BLBC. Combination treatment of BLBC cell lines with the EGFR-inhibitor gefitinib plus the PI3K pathway inhibitor LY294002 was synergistic, and correspondingly, in an in vivo BLBC xenograft mouse model, gefitinib plus PI3K-inhibitor PWT-458 was more effective than either monotherapy and caused tumor regression. CONCLUSIONS: Our study emphasizes the importance of PI3K/PTEN pathway activity in ER-negative and basal-like breast cancer and supports the future clinical evaluation of combining EGFR and PI3K pathway inhibitors for the treatment of BLBC. Gene expression profiles were generated for 95 breast tumors using Agilent Human 44K v5 microarrays following the manufacturer protocol. Stratagene Universal Human Reference RNA was used as the common control sample.
2016-08-21 | E-GEOD-74667 | biostudies-arrayexpress
Project description:15-25% of breast cancers (BC) show ERBB2-amplification and overexpression of the encoded ERBB2 tyrosine kinase receptor. They are associated with a poor prognosis but can benefit from targeted therapy. A better knowledge of these BCs may help understand their behavior and design new therapeutic strategies. In this study, we defined the high resolution genome and gene expression profiles of 54 ERBB2-amplified BCs using 244K oligonucleotide array-comparative genomic hybridization and whole-genome DNA microarrays. We first identified the ERBB2-C17orf37-GRB7 genomic segment as the minimal common amplicon, and CRKRS and IKZF3 as the most frequent centromeric and telomeric amplicon borders, respectively. Second, we identified 17 genome regions affected by copy number aberration (CNA). The expression of 37 genes of these regions was deregulated. Third, two types of heterogeneity were observed in ERBB2-amplified BCs. The genomic profiles of estrogen receptor-postive (ER+) and negative (ER-) ERBB2-amplified BCs were different. The WNT/Ã?-catenin signaling pathway was involved in ER- ERBB2-amplified BCs, and PVT1 and TRPS1 were candidate oncogenes associated with ER+ ERBB2-amplified BCs. The size of the ERBB2-amplicon was different in inflammatory (IBC) and non inflammatory BCs. ERBB2-amplified IBCs were characterized by the downregulated and upregulated mRNA expression of ten and two genes in proportion to CNA, respectively. We have shown that ERBB2 BCs are heterogeneous and identified genomic features that may be useful in the design of therapeutical strategies Tumor tissues were collected from 340 patients with invasive adenocarcinoma who underwent initial surgery at the Institut Paoli-Calmettes (Marseilles, France) between 1987 and 2007 (from a cohort of 2,175 patients with frozen tumor sample) and from a series of 91 Tunisian T4d tumors (TNM, UICC) treated between 1994 and 1998 at the Salah Azaiz Institute (Tunis, Tunisia). Each patient gave informed consent and the study was approved by our institutional review board. Samples were macrodissected and frozen in liquid nitrogen within 30 minutes of removal. Genomic imbalances were determined by aCGH using 244K CGH oligonucleotide microarrays (Hu-244A, Agilent Technologies). Gene expression data of 51 of the 54 BCs and 4 normal breast (NB) samples (NB1, NB2, NB3 and NB4, representing samples from 4 women and 3 commercial pools of respectively 1, 2 and 4 normal breast RNA, Clontech, Palo Alto, CA) were quantified by using whole-genome DNA microarrays (HG-U133 plus 2.0, Affymetrix).
2009-09-02 | E-GEOD-17907 | biostudies-arrayexpress
Project description:15-25% of breast cancers (BC) show ERBB2-amplification and overexpression of the encoded ERBB2 tyrosine kinase receptor. They are associated with a poor prognosis but can benefit from targeted therapy. A better knowledge of these BCs may help understand their behavior and design new therapeutic strategies. In this study, we defined the high resolution genome and gene expression profiles of 54 ERBB2-amplified BCs using 244K oligonucleotide array-comparative genomic hybridization and whole-genome DNA microarrays. We first identified the ERBB2-C17orf37-GRB7 genomic segment as the minimal common amplicon, and CRKRS and IKZF3 as the most frequent centromeric and telomeric amplicon borders, respectively. Second, we identified 17 genome regions affected by copy number aberration (CNA). The expression of 37 genes of these regions was deregulated. Third, two types of heterogeneity were observed in ERBB2-amplified BCs. The genomic profiles of estrogen receptor-postive (ER+) and negative (ER-) ERBB2-amplified BCs were different. The WNT/ß-catenin signaling pathway was involved in ER- ERBB2-amplified BCs, and PVT1 and TRPS1 were candidate oncogenes associated with ER+ ERBB2-amplified BCs. The size of the ERBB2-amplicon was different in inflammatory (IBC) and non inflammatory BCs. ERBB2-amplified IBCs were characterized by the downregulated and upregulated mRNA expression of ten and two genes in proportion to CNA, respectively. We have shown that ERBB2 BCs are heterogeneous and identified genomic features that may be useful in the design of therapeutical strategies
2009-09-02 | GSE17907 | GEO
Project description:Activating mutations of PIK3CA are the most frequent genomic alterations in estrogen receptor (ER)-positive breast tumors and selective PI3Kα inhibitors are in clinical development. The activity of these agents, however, is not homogenous and only a fraction of patients bearing PIK3CA-mutant ER-positive tumors benefit from single agent administration. Searching for mechanisms of resistance, we observed that suppression of PI3K signaling with different agents results in induction of ER-dependent transcriptional activity as demonstrated by changes in expression in genes containing ER binding sites, enhanced ER transcription and increased occupancy by the ER of promoter regions of upregulated genes. Furthermore, expression of ESR1 mRNA and ER protein levels themselves were also increased upon PI3K inhibition. These changes in gene expression were confirmed in vivo in xenograft and patient derived models and in tumors from patients undergoing treatment with the PI3Kα inhibitor BYL719. The observed effects on transcription were enhanced by the addition of estradiol and suppressed by the anti-ER therapies fulvestrant and tamoxifen. Fulvestrant markedly sensitized ER-positive tumors to PI3Kα inhibition. We propose that increased ER transcriptional activity may be a compensatory mechanism that limits the activity of PI3K inhibitors and that combined PI3K and ER inhibition is a rational approach to target these tumors. The aim of our study was to explore the mechanism by which combination of PI3K pathway inhibitors and estrogen receptor function blockade results in superior antitumor activity. We aimed to evaluate whether changes in ER function were influencing the clinical response to anti-PI3K therapy in ER-positive breast tumors that harbor PI3K pathway activation. For this purpose, we planned to use various specific PI3K inhibitors, namely: BYL719 (p110α specific catalytic inhibitor), GDC0941 (pan-PI3K inhibitor), GDC0032 and BAY80-6946 (p110sparing PI3K inhibitors) in a panel of ER-positive breast cancer cell lines and xenografts that harbor PIK3CA activating mutations. We also used MK2206 (pan-AKT allosteric inhibitor) to inhibit the PI3K pathway in ER-positive cell lines which activate this pathway through PTEN loss. Finally, in order to evaluate the role of ER up-regulation as a pro-survival signal in our in vitro and in vivo models, we planned to use the selective ER modulator 4-hydroxy-tamoxifen (4-OHT) and degrader fulvestrant. For the in vivo experiments, the number of animals in each group was calculated to measure a 25% difference between the means of placebo and treatment groups with a power of 80% and a p value of 0.01. Host mice carrying xenografts were randomly and equally assigned to either control or treatment groups. Animal experiments were conducted in a controlled and non-blinded manner. Moreover, we evaluated by means of RNAseq gene expression changes breast cancer patients that underwent BYL719 based therapy to validate our in vitro findings in terms of ER expression. In vitro experiments were performed at least two times and at least in triplicate for each replica.
2015-04-29 | E-GEOD-64033 | biostudies-arrayexpress
Project description:Integrative analysis of primary estrogen receptor-positive (ER+) breast cancer, triple-negative breast cancer (TNBC), and metaplastic breast cancer (MBC) tumors using Starfysh.
2024-02-10 | GSE218951 | GEO