Enhancement of ER function by PI3K inhibition limits the antitumor effects of PI3K inhibitors in breast cancer
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE63579 | GEO | 2015/04/15
SECONDARY ACCESSION(S): PRJNA268303
REPOSITORIES: GEO
Similar Datasets
Project description:Gene expression data of breast cancer samples before and after PI3K inhibition In the study presented here, we evaluated the expression profiles of a total of 105 unique genes in 6 breast cancer samples before and after PI3K-inhibitor therapy
2015-04-15 | E-GEOD-63579 | biostudies-arrayexpress
Project description:Activation of the phosphoinositide 3-kinase (PI3K)/Akt signaling pathway is one the most frequent genetic events in human cancer. Therefore, the development of PI3K inhibitors has attracted much attention. We previously described the pyrazolopyrimidine derivative ETP-45658 as a potent inhibitor of PI3K p110α in vitro and in vivo. Here we report the gene expression signatures of MCF7 cells treated with ETP-45658 or the reference PI3K inhibitor PI-103. Both compounds potently inhibited proliferation of a wide range of human cancer cells. ETP-45658 most potently suppressed the growth of PIK3CA (E545K)-mutated MCF7 breast cancer cells. Treatment with ETP-45658 or PI-103 resulted in a time and concentration-dependent decrease in phosphorylation of AKT Ser473 in MCF7 cells. We conducted microarray analysis examining the gene expression profile in MCF7 cells at six hours post ETP-45658 or PI-103 incubation. Both compounds induced the expression of negative cell cycle regulators including Cyclin G2, p27kip1 and ING4 and decreased positive regulators such as Cyclin D1 without significantly affecting the expression of pro-apoptotic genes. We found FOXO transcription factor binding sites over-represented in both up- and down-regulated genes but not in those without significant changes. The expression of the breast cancer tumor suppressor Nischarin was found to be induced by ETP-45658 but not after PI-103 treatment while several genes differentially expressed specifically after ETP-45658 treatment are functionally associated with the focal adhesion pathway. Twelve samples have been analyzed in six different conditions. Two replicates have been included for each condition.
2014-04-08 | E-GEOD-56579 | biostudies-arrayexpress
Project description:PI3K inhibition in ER+ breast cancer microarray data
| PRJNA114891 | ENA
Project description:Activation of the phosphoinositide 3-kinase (PI3K)/Akt signaling pathway is one the most frequent genetic events in human cancer. Therefore, the development of PI3K inhibitors has attracted much attention. We previously described the pyrazolopyrimidine derivative ETP-45658 as a potent inhibitor of PI3K p110α in vitro and in vivo. Here we report the gene expression signatures of MCF7 cells treated with ETP-45658 or the reference PI3K inhibitor PI-103. Both compounds potently inhibited proliferation of a wide range of human cancer cells. ETP-45658 most potently suppressed the growth of PIK3CA (E545K)-mutated MCF7 breast cancer cells. Treatment with ETP-45658 or PI-103 resulted in a time and concentration-dependent decrease in phosphorylation of AKT Ser473 in MCF7 cells. We conducted microarray analysis examining the gene expression profile in MCF7 cells at six hours post ETP-45658 or PI-103 incubation. Both compounds induced the expression of negative cell cycle regulators including Cyclin G2, p27kip1 and ING4 and decreased positive regulators such as Cyclin D1 without significantly affecting the expression of pro-apoptotic genes. We found FOXO transcription factor binding sites over-represented in both up- and down-regulated genes but not in those without significant changes. The expression of the breast cancer tumor suppressor Nischarin was found to be induced by ETP-45658 but not after PI-103 treatment while several genes differentially expressed specifically after ETP-45658 treatment are functionally associated with the focal adhesion pathway.
2014-04-08 | GSE56579 | 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:Combination therapy with Smo and PI3K inhibitors results in a synergistic effect in reducing tumor growth in PTEN-deficient Glioblastoma. To identify consequences of combination therapy with an Smo inhibitor and a PI3K inhibitor on a genome-wide scale, we performed Affymetrix microarrays with two different PTEN-deficient GBMs treated with single drugs or combination therapy. A small set of genes was significantly affected by combination therapy in hBT70 and/or hBT112, including several genes implicated in GBM prognosis, or identified as targets of Shh, PI3K or S6 pathways 29-33 . There are two different human GBM tumors (BT70 and BT112). Both are PTEN deficient. Samples were treated with DMSO (Control), LDE225 at 1 uM for 5 days, BKM 120 100 nM for 5 days, or LDE225 1 uM and BKM 120 100 nM for 5 days (Combo). Two biological replicates of each condition were analyzed.
2013-09-01 | E-GEOD-49416 | biostudies-arrayexpress
Project description:SUM52PE treated with PI3K-mTOR inhibitors
| PRJNA509669 | ENA
Project description:The phosphoinositide 3-kinase (PI3K) pathway integrates extracellular stimuli to phosphorylate and activate key downstream effectors such as AKT and serum-and glucocorticoid-inducible kinase (SGK1). We have previously reported that the PI3K pathway regulates ER-dependent transcription in breast cancer through the phosphorylation of the epigenetic regulator KMT2D by AKT. Here, we provide new insights into how the PI3K pathway propagates its effects to control KMT2D and ER function via SGK1, another PI3K downstream effector. Specifically, we show that PI3K inhibition, via a negative feedback loop, activates SGK1 to promote chromatin-based regulation of ER-dependent gene expression. PI3K/AKT inhibitors activate ER, which subsequently promotes SGK1 transcription through direct binding to its promoter. Elevated SGK1, in turn, phosphorylates KMT2D, suppressing its function and altering the chromatin landscape to attenuate ER-dependent expression. Thus, we have determined that SGK1 regulates the chromatin landscape and ER-dependent transcription via the direct phosphorylation of KMT2D. These findings reveal an ER-SGK1-KMT2D signaling circuit aimed to attenuate ER response through a previously unknown role for SGK1 to program chromatin and ER transcriptional output.
2019-04-02 | GSE119522 | GEO
Project description:Combination therapy with Smo and PI3K inhibitors results in a synergistic effect in reducing tumor growth in PTEN-deficient Glioblastoma. To identify consequences of combination therapy with an Smo inhibitor and a PI3K inhibitor on a genome-wide scale, we performed Affymetrix microarrays with two different PTEN-deficient GBMs treated with single drugs or combination therapy. A small set of genes was significantly affected by combination therapy in hBT70 and/or hBT112, including several genes implicated in GBM prognosis, or identified as targets of Shh, PI3K or S6 pathways 29-33 .
2013-09-01 | GSE49416 | GEO
Project description:PI3K/mTOR inhibition alters gene transcription signatures involved in metabolism and cell cycle control in the human breast cancer cell line, SUM52PE
2020-12-24 | GSE123740 | GEO