Activating Transcription Factor 4 modulated TGFb-induced aggresiveness in triple negative breast cancer vis SMAD2/3/4 and mTORC2 signaling
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE113362 | GEO | 2019/01/10
REPOSITORIES: GEO
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Project description:Triple negative breast cancer (TNBC) includes basal and non-basal subclasses. To further stratify TNBC we determined microRNA (miRNA) and mRNA expression profiles, linked specific miRNA signatures to patient survival and used miRNA/mRNA anti-correlations to identify TNBC subclasses associated with expression of canonical signal pathways
2013-04-19 | GSE41970 | GEO
Project description:Triple negative breast cancer (TNBC) includes basal and non-basal subclasses. To further stratify TNBC we determined microRNA (miRNA) and mRNA expression profiles, linked specific miRNA signatures to patient survival and used miRNA/mRNA anti-correlations to identify TNBC subclasses associated with expression of canonical signal pathways
2021-02-01 | GSE45498 | GEO
Project description:Triple-negative breast cancer (TNBC) is an aggressive subtype with few treatment options for chemo-resistant disease. In both preclinical models and patient circulating tumor cells, androgen receptor (AR) expression is increased in anchorage independent TNBC. The AR inhibitor enzalutamide (Enza) leads to reduced TNBC growth in soft agar, invasion, mammosphere formation in vitro, and reduced tumorigenicity and recurrence when combined with chemotherapy in vivo pre-clinical models. Transforming growth factor β (TGFβ) pathway gene signatures are also increased during TNBC anchorage independent survival both in vitro and in vivo in pre-clinical models and CTC from patients during relapse while on chemotherapy. We hypothesized that a positive loop between AR and TGFβ signaling facilitates TNBC anchorage independent survival (anoikis resistance). We previously published that AR protein levels and transcriptional activity increased during anchorage independent conditions and we now find that that multiple components of the TGFβ pathway, including TGFβ1 and 3, as well as pathway activity, as measured by nuclear localization and transcriptional activity of pSmad3, are enhanced in anchorage independent conditions. Indeed, exogenous TGFβ increased AR protein and TGFβ inhibition decreased AR and TNBC viability, particularly under anchorage independent culture conditions. ChIP-Seq experiments revealed AR binding to genomic regions near the TGFB1 and SMAD3. TGFB3 and AR expression were positively correlated in clinical datasets and high levels of co-expression correspond to significantly worse recurrence-free and overall survival in both ER- and basal-like breast cancer. Finally, combining Enza with a TGFβ inhibitor decreased cell survival more than either drug alone, particularly under anchorage independent conditions, where the effect was more than additive. These findings warrant further investigations into whether combined inhibition of AR and TGFβ pathways might decrease metastatic recurrence rates and mortality from TNBC.
2021-11-10 | GSE157862 | GEO
Project description:We report the application of ChIP-seq, which combines chromatin immunoprecipitation (ChIP) with massively parallel DNA sequencing, to map genome-wide XBP1 binding sites in different breast cancer cell lines. We showed that HIF1M-NM-1 motif was enriched in XBP1 binding sites in triple negative breast cancer (TNBC) cell lines, but not enriched in ER positive breast cancer cell line. We also demonstrated that different breast cancer cell lines of the same sub-type had similar XBP1 binding sites, whereas different breast cancer sub-types had majorly different XBP1 binding sites. Finally, a model was applied to integrate XBP1 ChIP-seq data with expression data to predict XBP1's direct targets in TNBC cell line; the predicted direct targets were shown to be predictive of patient survival, and the prediction power was specific to TNBC patients. The above evidence indicates that XBP1 performs important functions in TNBC by interacting with HIF1M-NM-1, and such regulation mechanism is specific to TNBC, which is later proved by follow-up experiments.This study represents the first detailed anaysis of XBP1 binding sites in different breast cancer cell lines. Examination of XBP1 binding sites in 2 cell types (3 cell lines).
2013-09-26 | E-GEOD-49952 | biostudies-arrayexpress
Project description:Altered signaling pathways typify breast cancer and serve as direct inputs to steroid hormone receptor sensors. We previously reported that phospho-Ser134-GR (pS134-GR) species are elevated in triple negative breast cancer (TNBC) and cooperate with hypoxia-inducible factors, providing a novel avenue for activation of GR in response to local or cellular stress. We probed GR regulation by factors (cytokines, growth factors) that are rich within the tumor microenvironment (TME). TNBC cells harboring endogenous wild-type (wt) or S134A-GR species were created by CRISPR/Cas knock-in and subjected to transwell migration, invasion, soft-agar colony formation, and tumorsphere assays. RNA-Seq was employed to identify pS134-GR target genes that are regulated both basally (intrinsic) or by TGFβ in the absence of exogenously added GR ligands. Regulation of selected basal and TGFβ-induced pS134-GR target genes was validated by qRT-PCR and chromatin immunoprecipitation assays. Bioinformatics tools were used to probe public data sets for expression of pS134-GR 24-gene signatures. In the absence of GR ligands, GR is transcriptionally activated via p38-dependent phosphorylation of Ser134 as a mechanism of homeostatic stress-sensing and regulated upon exposure of TNBC cells to TME-derived agents. The ligand-independent pS134-GR transcriptome encompasses TGFβ1 and MAPK signaling gene sets associated with TNBC cell survival and migration/invasion. Accordingly, pS134-GR was essential for TNBC cell anchorage-independent growth in soft-agar, migration, invasion, and tumorsphere formation, an in vitro readout of cancer stemness properties. Both pS134-GR and expression of the MAPK-scaffolding molecule 14-3-3ζ were essential for a functionally intact p38 MAPK signaling pathway downstream of MAP3K5/ASK1, indicative of a feed-forward signaling loop wherein self-perpetuated GR phosphorylation enables cancer cell autonomy. A 24-gene pS134-GR-dependent signature induced by TGFβ1 predicts shortened overall survival in breast cancer patients. Phospho-S134-GR is a critical downstream effector of p38 MAPK signaling and TNBC migration/invasion, survival, and stemness properties. Our studies define a ligand-independent role for GR as a homeostatic “sensor” of intrinsic stimuli as well as extrinsic factors rich within the TME (TGFβ1) that enables potent activation of the p38 MAPK stress-sensing pathway and nominate pS134-GR as a therapeutic target in aggressive TNBC.
2020-05-01 | GSE148444 | GEO
Project description:Triple negative breast cancer (TNBC) includes basal and non-basal subclasses. To further stratify TNBC we determined microRNA (miRNA) and mRNA expression profiles, linked specific miRNA signatures to patient survival and used miRNA/mRNA anti-correlations to identify TNBC subclasses associated with expression of canonical signal pathways RNA was isolated from formalin-fixed paraffin-embedded tissue cores of 165 primary tumors, 59 adjacent normal and 54 lymph node metastatic samples and expression of 664 miRNAs and 230 cancer-associated mRNAs was assessed for each sample using the nanoString nCounter platform. Kaplan-Meier distant-disease free and overall survival curves were compared using the log-rank test. Cox proportional hazard regression and risk score analysis were used to identify miRNAs for classification of patients with significantly different prognoses.
2013-04-19 | E-GEOD-41970 | biostudies-arrayexpress
Project description:Activating Transcription Factor 4 modulated TGFb-induced aggresiveness in triple negative breast cancer vis SMAD2/3/4 and mTORC2 signaling
| PRJNA450921 | ENA
Project description:Triple negative breast cancer (TNBC) is an aggressive subtype that lack targeted clinical therapies. In addition, TNBC is heterogeneous and was recently further sub-classified into seven TNBC subtypes that displayed unique gene expression patterns. To develop therapeutic treatment regimens, we established seven patient-derived xenograft models from TNBC tumors. These xenograft models not only retained the histology and clinical markers of the corresponding patient tumors, but also bearing the same mutations and deletions identified in the patient tumors. Moreover, as part of evaluation of these models, we performed microarrays on the xenograft tumors to assess their TNBC subtypes. After obtaining IRB-approved informed written patient consent, breast cancer tissues were obtained fresh from Stanford Hospital and transplanted into the number 2 mammary fat pads of female NOD SCID mice (NOD.CB17-Prkdcscid/J, Jackson Laboratory West, Sacramento, CA, USA). Mice were maintained in pathogen-free animal housing. The established xenografts were subsequently passaged from mouse to mouse. Xenograft tumor tissues were frozen on dry ice for RNA isolation and microarray analysis.
2014-03-21 | E-GEOD-47079 | biostudies-arrayexpress
Project description:Breast cancer (BC) is a highly heterogeneous disease, both at the pathological and molecular level, and several chromatin-associated proteins play crucial roles in breast cancer initiation and progression. Here, we demonstrate the role of PSIP1 (PC4 and SF2 interacting protein)/p75 (LEDGF) in breast cancer progression. PSIP1/p75, previously identified as a chromatin-adaptor protein, is found to be upregulated in basal-like/triple negative breast cancer (TNBC) patient samples and cell lines. Immunohistochemistry in tissue arrays showed elevated levels of PSIP1 in metastatic invasive ductal carcinoma. Survival data analyses indicated that the levels of PSIP1 showed a negative association with TNBC patient survival. Depletion of PSIP1/p75 significantly reduced the tumorigenicity and metastatic properties of TNBC cell lines while its over-expression promoted tumorigenicity. Further, gene expression studies revealed that PSIP1 regulates the expression of genes controlling cell-cycle progression, cell migration, and invasion. Finally, by interacting with RNA polymerase II, PSIP1/p75 facilitates the association of RNA pol II to the promoter of cell cycle genes and thereby regulates their transcription. Our findings demonstrate an important role of PSIP1/p75 in TNBC tumorigenicity by promoting the expression of genes that control the cell cycle and tumor metastasis.
2017-06-06 | GSE99699 | GEO
Project description:Age-related impairment of macroautophagy/autophagy and loss of cardiac tissue homeostasis contribute significantly to cardiovascular diseases later in life. MTOR (mechanistic target of rapamycin kinase) signaling is the most well-known regulator of autophagy, cellular homeostasis, and longevity. The MTOR signaling consists of two structurally and functionally distinct multiprotein complexes, MTORC1 and MTORC2. While MTORC1 is well characterized but the role of MTORC2 in aging and autophagy remains poorly understood. Here we identified TGFB-INHB/activin signaling as a novel upstream regulator of MTORC2 to control autophagy and cardiac health during aging. Using Drosophila heart as a model system, we show that cardiac-specific knockdown of TGFB-INHB/activin-like protein daw induces autophagy and alleviates age-related heart dysfunction, including cardiac arrhythmias and bradycardia. Interestingly, the downregulation of daw activates TORC2 signaling to regulate cardiac autophagy. Activation of TORC2 alone through overexpressing its subunit protein rictor promotes autophagic flux and preserves cardiac function with aging. In contrast, activation of TORC1 does not block autophagy induction in daw knockdown flies. Lastly, either daw knockdown or rictor overexpression in fly hearts prolongs lifespan, suggesting that manipulation of these pathways in the heart has systemic effects on longevity control. Thus, our studies discover the TGFB-INHB/activin-mediated inhibition of TORC2 as a novel mechanism for age-dependent decreases in autophagic activity and cardiac health. Abbreviations: AI: arrhythmia index; BafA1: bafilomycin A1; BMP: bone morphogenetic protein; CQ: chloroquine; CVD: cardiovascular diseases; DI: diastolic interval; ER: endoplasmic reticulum; HP: heart period; HR: heart rate; MTOR: mechanistic target of rapamycin kinase; NGS: normal goat serum; PBST: PBS with 0.1% Triton X-100; PDPK1: 3-phosphoinositide dependent protein kinase 1; RICTOR: RPTOR independent companion of MTOR complex 2; ROI: region of interest; ROUT: robust regression and outlier removal; ROS: reactive oxygen species; R-SMAD: receptor-activated SMAD; SI: systolic interval; SOHA: semi-automatic optical heartbeat analysis; TGFB: transformation growth factor beta; TSC1: TSC complex subunit 1.
| S-EPMC8386626 | biostudies-literature