PI3K/AKT signaling regulates H3K4 methylation in breast cancer
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE80594 | GEO | 2016/06/14
SECONDARY ACCESSION(S): PRJNA319402
REPOSITORIES: GEO
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Project description:This SuperSeries is composed of the SubSeries listed below. Refer to individual Series
2016-06-14 | E-GEOD-80594 | biostudies-arrayexpress
Project description:Post-translational histone H3 modifications regulate transcriptional competence. The mechanisms by which the epigenome is regulated in response to oncogenic signaling remain unclear. Here we show that H3K4me3 is increased in breast tumors driven by an activated PIK3CA allele and that inhibition of PI3K/AKT signaling reduces promoter-associated H3K4me3 in human breast cancer cells. We show that the H3K4 demethylase KDM5A is an AKT target and that phosphorylation of KDM5A regulates its nuclear localization and promoter occupancy. Supporting a role for KDM5A in mediating PI3K/AKT transcriptional effects, the decreased expression in response to AKT inhibition of a subset of cell-cycle genes associated with poor clinical outcome is blunted by KDM5A silencing. Our data identify a mechanism by which PI3K/AKT signaling modulates the cancer epigenome through controlling H3K4 methylation and suggest that KDM5A subcellular localization and genome occupancy may be pharmacodynamic markers of the activity of PI3K/AKT inhibitors currently in clinical development.
| S-EPMC5094353 | biostudies-literature
Project description:PI3K/AKT signaling regulates H3K4 methylation in breast cancer
| PRJNA319402 | ENA
Project description:Over 70% of breast cancers express the estrogen receptor (ER) and depend on ER activity for survival and proliferation. While hormone therapies that target receptor activity are initially effective, patients invariably develop resistance which is often associated with activation of the phosphoinositide 3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) pathway. While the mechanism by which estrogen regulates proliferation is not fully understood, one gene target of ER, growth regulation by estrogen in breast cancer 1 (GREB1), is required for hormone-dependent proliferation. However, the molecular function by which GREB1 regulates proliferation is unknown. Herein, we validate that knockdown of GREB1 results in growth arrest and that exogenous GREB1 expression initiates senescence, suggesting that an optimal level of GREB1 expression is necessary for proliferation of breast cancer cells. Under both of these conditions, GREB1 is able to regulate signaling through the PI3K/Akt/mTOR pathway. GREB1 acts intrinsically through PI3K to regulate phosphatidylinositol (3,4,5)-triphosphate levels and Akt activity. Critically, growth suppression of estrogen-dependent breast cancer cells by GREB1 knockdown is rescued by expression of constitutively activated Akt. Together, these data identify a novel molecular function by which GREB1 regulates breast cancer proliferation through Akt activation and provides a mechanistic link between estrogen signaling and the PI3K pathway.
| S-EPMC7791615 | biostudies-literature
Project description:Recent evidences have shown that glycoprotein V (GP5) protein, which is initially considered as an important adhesion molecule unique to the megakaryocyte line, was also specifically expressed in malignant human breast epithelial cells. However, its expression level and function are not clear. This study aimed to reveal the abnormal expression of GP5 in breast cancer (BC), research the associations between the GP5 abnormal expression and BC progression, and explore the molecular mechanism of GP5 in BC. Immunohistochemistry, Western blot (WB), and quantitative reverse transcription-polymerase chain reaction (RT-PCR) assays were used to determine the expression patterns of GP5 in BC tissues and cells. The expression profiles of GP5 in the Cancer Genome Atlas databases were analyzed by UALCAN. The GP5 knockdown and over-expression BC cell lines were constructed and confirmed by RT-PCR and WB. Transcriptome sequencing and KEGG database were performed to screen cellular processes and signal pathways. Phosphatidylinositol 3-kinase (PI3K)/AKT pathway was verified by RT-qPCR, and epithelial-mesenchymal transition (EMT) was confirmed by WB. The results indicated GP5 was highly expressed in BC tissues and might play an important role as a cancer-promoting gene in BC. The high expression of GP5 was significantly associated with higher nuclear grade, higher TNM stage, and human epidermal growth factor receptor 2 (HER2) negativity. GP5 may promote the proliferation, invasion, and metastasis of BC cells by activating PI3K/AKT signaling pathway to up-regulate the EMT. This study provides a new idea that GP5 was expected to become a potential molecular target for early BC clinic diagnosis and treatment.
| S-EPMC9554163 | biostudies-literature
Project description:Breast cancer is the most frequently diagnosed cancer and the primary cause of cancer death in women worldwide. Although early diagnosis and cancer growth inhibition has significantly improved breast cancer survival rate over the years, there is a current need to develop more effective systemic treatments to prevent metastasis. One of the most commonly altered pathways driving breast cancer cell growth, survival, and motility is the PI3K/AKT/mTOR signaling cascade. In the past 30 years, a great surge of inhibitors targeting these key players has been developed at a rapid pace, leading to effective preclinical studies for cancer therapeutics. However, the central role of PI3K/AKT/mTOR signaling varies among diverse biological processes, suggesting the need for more specific and sophisticated strategies for their use in cancer therapy. In this review, we provide a perspective on the role of the PI3K signaling pathway and the most recently developed PI3K-targeting breast cancer therapies.
| S-EPMC8304822 | biostudies-literature
Project description:This SuperSeries is composed of the SubSeries listed below. Refer to individual Series
2015-02-20 | E-GEOD-57719 | biostudies-arrayexpress
Project description:BackgroundCaseinolytic protease P (ClpP), which is located on the inner mitochondrial membrane, degrades mitochondrial proteins damaged by oxidative stress. The role of ClpP varies among tumor types. However, the expression pattern and biological functions of ClpP in breast cancer (BC) have not yet been investigated.MethodsThe Cancer Genome Atlas (TCGA) and Kaplan Meier-plotter database were used to analyze the expression level of ClpP in BC tissues, relationships with clinicopathological characteristics, and the influence on the prognosis of BC. Protein and mRNA expression levels of ClpP in BC cell lines and tissues were detected by quantitative real-time PCR, western blot and immunohistochemical (IHC) analyses. The colony formation assay, transwell assay and flow cytometric analysis were performed to assess various functions of ClpP. Western blot analysis was also conducted to determine the mechanism of ClpP.ResultsClpP expression was markedly increased in BC cells and tissues. High expression of ClpP was significantly correlated with the T stage, estrogen receptor (ER) expression, and poor recurrence-free survival (RFS) in TCGA and Kaplan Meier-plotter database. ClpP silencing significantly inhibited proliferation, migration, invasion, and promoted apoptosis of BC cells, which resulted in suppression of the Src/PI3K/Akt signaling pathway. The gain-of-function assay confirmed partial these results.
| S-EPMC7069407 | biostudies-literature
Project description:Trimethylation of histone 3 lysine 27 (H3K27me3) is a critical epigenetic mark for the maintenance of gene silencing. Additional accumulation of DNA methylation in target loci is thought to cooperatively support this epigenetic silencing during tumorigenesis. However, molecular mechanisms underlying the complex interplay between the two marks remain to be explored. Here we show that activation of PI3K/AKT signaling can be a trigger of this epigenetic processing at many downstream target genes. We also find that DNA methylation can be acquired at the same loci in cancer cells, thereby reinforcing permanent repression in those losing the H3K27me3 mark. Because of a link between PI3K/AKT signaling and epigenetic alterations, we conducted epigenetic therapies in conjunction with the signaling-targeted treatment. These combined treatments synergistically relieve gene silencing and suppress cancer cell growth in vitro and in xenografts. The new finding has important implications for improving targeted cancer therapies in the future.
| S-EPMC3048165 | biostudies-literature
Project description:PurposeThe PI3K/Akt signaling axis contributes to the dysregulation of many dominant features in breast cancer including cell proliferation, survival, metabolism, motility, and genomic instability. While multiple studies have demonstrated that basal-like or triple-negative breast tumors have uniformly high PI3K/Akt activity, genomic alterations that mediate dysregulation of this pathway in this subset of highly aggressive breast tumors remain to be determined.MethodsIn this study, we present an integrated genomic analysis based on the use of a PI3K gene expression signature as a framework to analyze orthogonal genomic data from human breast tumors, including RNA expression, DNA copy number alterations, and protein expression. In combination with data from a genome-wide RNA-mediated interference screen in human breast cancer cell lines, we identified essential genetic drivers of PI3K/Akt signaling.ResultsOur in silico analyses identified SOX4 amplification as a novel modulator of PI3K/Akt signaling in breast cancers and in vitro studies confirmed its role in regulating Akt phosphorylation.ConclusionsTaken together, these data establish a role for SOX4-mediated PI3K/Akt signaling in breast cancer and suggest that SOX4 may represent a novel therapeutic target and/or biomarker for current PI3K family therapies.
| S-EPMC5334195 | biostudies-literature