Metabolomics,Unknown,Transcriptomics,Genomics,Proteomics

Dataset Information

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: clairac geraldine

PROVIDER: E-GEOD-22035 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Publications

Gene expression profiling reveals new aspects of PIK3CA mutation in ERalpha-positive breast cancer: major implication of the Wnt signaling pathway.

Cizkova Magdalena M Cizeron-Clairac Géraldine G Vacher Sophie S Susini Aurélie A Andrieu Catherine C Lidereau Rosette R Bièche Ivan I

PloS one 20101230 12

<h4>Background</h4>The PI3K/AKT pathway plays a pivotal role in breast cancer development and maintenance. PIK3CA, encoding the PI3K catalytic subunit, is the oncogene exhibiting a high frequency of gain-of-function mutations leading to PI3K/AKT pathway activation in breast cancer. PIK3CA mutations have been observed in 30% to 40% of ERα-positive breast tumors. However the physiopathological role of PIK3CA mutations in breast tumorigenesis remains largely unclear.<h4>Methodology/principal findin ...[more]

PMID: 21209903

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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 (p110sparing 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.

Project description:Hyperactivation of the PI3K/AKT pathway is observed in most NSCLCs, promoting proliferation, migration and resistance to therapy. AKT can be activated through several mechanisms that include loss of the negative regulator PTEN, activating mutations of the catalytic subunit of the positive regulator phosphatydil-inositol-3â phosphate kinase (PIK3CA) and/or mutations of AKT1 itself. However, whereas the effects of AKT activation on mRNAs and proteins in the cell are fairly clear, the role of miRNAs as downstream targets of activated PI3K/AKT signalling is still poorly defined so far. To identify miRNAs that are targets of constitutive signalling of PI3K/AKT in lung cancer cells, we performed miRNA profiling of human lung epithelial cells expressing active mutant AKT1 (E17K), active mutant PI3KCA (E545K) or that are silenced for PTEN. We identified 28 differentially expressed miRNAs (8 up-regulated, 20 down-regulated) that were common to BEAS-AKT1-E17K, BEAS-PIK3CA-E545K and BEAS-shPTEN cells. Among the 8 up-regulated miRNAs that were common to all the alterations, the miRNA most consistently up-regulated by activation of the PI3K/AKT pathway in BEAS-2B cells was miR-196a. The results reported here demonstrate that miR-196a acts as oncogene downstream the PI3K/AKT pathway, mediating the proliferative, pro-migratory and tumorigenic activity of this pathway in NSCLC cells by targeting FoxO1 and p27 expression. By adoptive expression of miR-196a in BEAS-2B cells, we demonstrated that miR-196a stimulates anchorage-dependent and -independent proliferation, migration and tumorigenicity in BEAS-2B cells. On the other hand, by use of antimir-196a in NCI-H460 cells to silence the endogenous expression of miR-196a, we demonstrate that miR-196a plays a pivotal role in mediating the stimulation of proliferation, migration and tumorigenicity induced by aberrant activation of PI3K/AKT signalling. Accordingly, we found that miR-196a was significantly overexpressed in human NSCLC-derived cell lines (n=6) and primary lung cancer samples (n=28). Finally, based on predicted binding sites for miR-196a by microRNA analysis software, we found that miR-196a affects protein levels of FoxO1 and p27 in NSCLC cells.

Dataset Information

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

Publications

Gene expression profiling reveals new aspects of PIK3CA mutation in ERalpha-positive breast cancer: major implication of the Wnt signaling pathway.

Similar Datasets

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