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Transcription profiling by array of human estrogen receptor alpha positive breast tumors with and without PIK3CA mutations

ABSTRACT: PI3K/AKT pathway plays one of pivotal roles in breast cancer development and maintenance. PIK3CA, coding PIK3 catalytic subunit, is the oncogene which shows the high frequency of gain-of-function mutations leading to the PI3K/AKT pathway activation in breast cancer. In particular in the ERα-positive breast tumors PIK3CA mutations have been observed in 30% to 40%. However, genes expressed in connection to the pathway activation in breast tumorigenesis remain largely unknown. To identify downstream relevant target genes (and signaling pathways) turned on by the aberrant PI3K/AKT signal in breast tumors, we analyzed gene expression by pangenomic oligonucleotide microarray in a series of 43 ERα-positive tumors with and without PIK3CA mutations. 43 ERα-positive breast tumors including 14 tumors with PIK3CA mutations and 29 tumors without PIK3CA mutattions were used as screening set for microarray.

ORGANISM(S): Homo sapiens

SUBMITTER: Cizkova M

PROVIDER: S-ECPF-GEOD-22035 | biostudies-other | 2010

REPOSITORIES: biostudies-other

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Transcription profiling by array of human estrogen receptor alpha positive breast tumors with and without PIK3CA mutations.

Project description:PI3K/AKT pathway plays one of pivotal roles in breast cancer development and maintenance. PIK3CA, coding PIK3 catalytic subunit, is the oncogene which shows the high frequency of gain-of-function mutations leading to the PI3K/AKT pathway activation in breast cancer. In particular in the ERα-positive breast tumors PIK3CA mutations have been observed in 30% to 40%. However, genes expressed in connection to the pathway activation in breast tumorigenesis remain largely unknown. To identify downstream relevant target genes (and signaling pathways) turned on by the aberrant PI3K/AKT signal in breast tumors, we analyzed gene expression by pangenomic oligonucleotide microarray in a series of 43 ERα-positive tumors with and without PIK3CA mutations. 43 ERα-positive breast tumors including 14 tumors with PIK3CA mutations and 29 tumors without PIK3CA mutattions were used as screening set for microarray.

2011-01-10 | E-GEOD-22035 | biostudies-arrayexpress

Gene expression data in estrogen receptor alpha positive breast tumors with and without PIK3CA mutations.

2011-01-10 | GSE22035 | GEO

Transcription profiling by array of human estrogen receptor positive breast cancer cell lines after long-term estrogen deprivation

Project description:Hyperactivation of phosphatidylinositol-3 kinase (PI3K) promotes escape from hormone dependence in estrogen receptor-positive breast cancer. A significant fraction of breast cancers exhibit de novo or acquired resistance to estrogen deprivation. We used gene expression microarrays to identify genes and pathways that are commonly dysregulated in ER+ cell lines with acquired hormone-independent growth. MCF-7, ZR75-1, MDA-361, and HCC-1428 ER+, estrogen-responsive breast cancer cells were cultured under hormone-depleted conditions (10% DCC-FBS) for several months until sustainable hormone-independent cell populations emerged. Parental and long-term estrogen-deprived (LTED) cells were treated with 10% dextran-coated charcoal-treated fetal bovine serum (DCC-FBS) x 24 hrs prior to RNA harvest for array analysis.

| S-ECPF-GEOD-19639 | biostudies-other

Transcription profiling by array of human pancreatic tumors

Project description:We used microarrays to identify the expression differences of FKBP5 gene between the pancreatic tumor and normal samples. On average normal samples had more FKBP5 expression compared to tumor samples .Experiment Overall Design: This experiment consists of 36 tumor samples and 16 normal samples; a total of 52 samples. 16 samples consist of both tumor and normal expression data, whereas 20 samples consist of only tumor data.

| S-ECPF-GEOD-16515 | biostudies-other

Transcription profiling by array of human MCF cells treated with estrogen

Project description:The estrogen receptor is the master transcriptional regulator of breast cancer phenotype and the archetype of a molecular therapeutic target. We mapped all estrogen receptor and RNA polymerase II binding sites on a genome-wide scale, identifying the authentic cis binding sites and target genes, in breast cancer cells. Combining this unique resource with gene expression data demonstrates distinct temporal mechanisms of estrogen-mediated gene regulation,particularly in the case of estrogen-suppressed genes. Furthermore, this resource has allowed the identification of cis-regulatory sites in previously unexplored regions of the genome and the cooperating transcription factors underlying estrogen signaling in breast cancer. Experiment Overall Design: This Series currently contains the gene expression data accompaning Carroll JS et al. Nature Genetics 38,1289-1297(2006). MCF7 cells were stimulated with 100 nM estrogen for 0, 3, 6, or 12h. All experiments were performed in triplicate.

| S-ECPF-GEOD-11324 | biostudies-other

Emergence of constitutively active estrogen receptor-α mutations in pretreated advanced estrogen receptor-positive breast cancer.

Project description:PurposeWe undertook this study to determine the prevalence of estrogen receptor (ER) α (ESR1) mutations throughout the natural history of hormone-dependent breast cancer and to delineate the functional roles of the most commonly detected alterations.Experimental designWe studied a total of 249 tumor specimens from 208 patients. The specimens include 134 ER-positive (ER(+)/HER2(-)) and, as controls, 115 ER-negative (ER(-)) tumors. The ER(+) samples consist of 58 primary breast cancers and 76 metastatic samples. All tumors were sequenced to high unique coverage using next-generation sequencing targeting the coding sequence of the estrogen receptor and an additional 182 cancer-related genes.ResultsRecurring somatic mutations in codons 537 and 538 within the ligand-binding domain of ER were detected in ER(+) metastatic disease. Overall, the frequency of these mutations was 12% [9/76; 95% confidence interval (CI), 6%-21%] in metastatic tumors and in a subgroup of patients who received an average of 7 lines of treatment the frequency was 20% (5/25; 95% CI, 7%-41%). These mutations were not detected in primary or treatment-naïve ER(+) cancer or in any stage of ER(-) disease. Functional studies in cell line models demonstrate that these mutations render estrogen receptor constitutive activity and confer partial resistance to currently available endocrine treatments.ConclusionsIn this study, we show evidence for the temporal selection of functional ESR1 mutations as potential drivers of endocrine resistance during the progression of ER(+) breast cancer.

| S-EPMC3998833 | biostudies-literature

PIK3CA C-terminal frameshift mutations are novel oncogenic events that sensitize tumors to PI3K-α inhibition.

Project description:PIK3CA hotspot mutation is well established as an oncogenic driver event in cancer and its durable and efficacious inhibition is a focus in the development and testing of clinical cancer therapeutics. However, hundreds of cancer-associated PIK3CA mutations remain uncharacterized, their sensitivity to PI3K inhibitors unknown. Here, we describe a series of PIK3CA C-terminal mutations, primarily nucleotide insertions, that produce a frame-shifted protein product with an extended C terminus. We report that these mutations occur at a low frequency across multiple cancer subtypes, including breast, and are sufficient to drive oncogenic transformation in vitro and in vivo. We demonstrate that the oncogenicity of these mutant p110α proteins is dependent on p85 but not Ras association. P110α-selective pharmacologic inhibition blocks transformation in cells and mammary tumors characterized by PIK3CA C-terminal mutation. Taken together, these results suggest patients with breast and other tumors characterized by PIK3CA C-terminal frameshift mutations may derive benefit from p110α-selective inhibitors, including the recently FDA-approved alpelisib.

| S-EPMC7533832 | biostudies-literature

Transcription profiling by array of human HhAntag-treated pancreatic xenograft tumors

Project description:Four vehicle-treated and four HhAntag-treated pancreatic xenograft tumors were profiled for gene expression changes using Affymetrix U133 Plus 2.0 and Affymetrix Mouse Genome 430 2.0 arrays. Keywords: comparative gene expression, hedgehog, hh A primary human pancreatic tumor xenograft (1051178-A) was established by direct implantation of surgical material into female CD1 nu/nu mice of 6-8 weeks of age. Tumors were serially passaged into larger cohorts of mice for efficacy testing and subsequently distributed into tumor volume-matched cohorts upon tumors reaching between 200 to 350 mm3. HhAntag was resuspended in 0.5% methyl-cellulose, 0.2% Tween-80 (MCT) and administered orally twice daily at 75 mg/kg from a 10 mg/ml suspension. MCT alone served as vehicle control. Tumor xenografts (4/group) were excised following 21 days of dosing and RNA was extracted. Preparation of complementary RNA, Human Genome U133 Plus 2.0 array and Mouse Genome 430 2.0 array hybridizations, and subsequent data analysis were carried out using Affymetrix protocols, with signal intensities being determined by the MAS5.0 algorithm.

| S-ECPF-GEOD-11981 | biostudies-other

PIK3CA mutations associated with gene signature of low mTORC1 signaling and better outcomes in estrogen receptor-positive breast cancer.

Project description:PIK3CA mutations are reported to be present in approximately 25% of breast cancer (BC), particularly the estrogen receptor-positive (ER+) and HER2-overexpressing (HER2+) subtypes, making them one of the most common genetic aberrations in BC. In experimental models, these mutations have been shown to activate AKT and induce oncogenic transformation, and hence these lesions have been hypothesized to render tumors highly sensitive to therapeutic PI3K/mTOR inhibition. By analyzing gene expression and protein data from nearly 1,800 human BCs, we report that a PIK3CA mutation-associated gene signature (PIK3CA-GS) derived from exon 20 (kinase domain) mutations was able to predict PIK3CA mutation status in two independent datasets, strongly suggesting a characteristic set of gene expression-induced changes. However, in ER+/HER2- BC despite pathway activation, PIK3CA mutations were associated with a phenotype of relatively low mTORC1 signaling and a good prognosis with tamoxifen monotherapy. The relationship between clinical outcome and the PIK3CA-GS was also assessed. Although the PIK3CA-GS was not associated with prognosis in ER- and HER2+ BC, it could identify better clinical outcomes in ER+/HER2- disease. In ER+ BC cell lines, PIK3CA mutations were also associated with sensitivity to tamoxifen. These findings could have important implications for the treatment of PIK3CA-mutant BCs and the development of PI3K/mTOR inhibitors.

| S-EPMC2890442 | biostudies-literature

Mutational profiling reveals PIK3CA mutations in gallbladder carcinoma.

Project description:BackgroundThe genetics of advanced biliary tract cancers (BTC), which encompass intra- and extra-hepatic cholangiocarcinomas as well as gallbladder carcinomas, are heterogeneous and remain to be fully defined.MethodsTo better characterize mutations in established known oncogenes and tumor suppressor genes we tested a mass spectrometric based platform to interrogate common cancer associated mutations across a panel of 77 formalin fixed paraffin embedded archived BTC cases.ResultsMutations among three genes, KRAS, NRAS and PIK3CA were confirmed in this cohort. Activating mutations in PIK3CA were identified exclusively in GBC (4/32, 12.5%). KRAS mutations were identified in 3 (13%) intra-hepatic cholangiocarcinomas and 1 (33%) perihillar cholangiocarcinoma but were not identified in gallbladder carcinomas and extra-hepatic cholangiocarcinoma.ConclusionsThe presence of activating mutations in PIK3CA specifically in GBC has clinical implications in both the diagnosis of this cancer type, as well as the potential utility of targeted therapies such as PI3 kinase inhibitors.

| S-EPMC3045359 | biostudies-literature

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