Gene expression signature after γklotho knockdown in HCC1395 triple negative breast cancer cells
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE69082 | GEO | 2015/12/01
SECONDARY ACCESSION(S): PRJNA284497
REPOSITORIES: GEO
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Project description:Triple-negative breast cancer (TNBC) is a highly aggressive form of breast cancer that exhibits extremely high levels of genetic complexity and yet a relatively uniform transcriptional program. We postulate that TNBC might be highly dependent on uninterrupted transcription of a key set of genes within this gene expression program and might therefore be exceptionally sensitive to inhibitors of transcription. Utilizing a novel kinase inhibitor and CRISPR/Cas9-mediated gene editing, we show here that triple-negative but not ER/PR+ breast cancer cells are exceptionally dependent on CDK7, a transcriptional cyclin-dependent kinase. TNBC cells are unique in their dependence on this transcriptional CDK and suffer apoptotic cell death upon CDK7 inhibition. An “Achilles cluster” of TNBC-specific genes are extremely sensitive to CDK7 inhibition and frequently associated with super-enhancers. We conclude that CDK7 mediates transcriptional addiction to a vital cluster of genes in TNBC and CDK7 inhibition may be useful therapy for this challenging cancer. Expression microarrays in H3K27ac in triple-negative breast cancer +/- treatment with covalent CDK7 inhibitor THZ1 treatment
2015-09-24 | E-GEOD-69106 | biostudies-arrayexpress
Project description:Breast cancer is genetically and clinically heterogeneous. Triple negative cancer (TNBC) is a subtype of breast cancer usually associated with poor outcome and lack of benefit from target therapy. A pathway analysis in a microarray study was performed using TNBC compared with non-triple negative breast cancer (non-TNBC). Overexpression of several Wnt pathway genes, such as frizzled homolog 7 (FZD7), Low density lipoprotein receptor-related protein 6 (LRP6) and transcription factor 7 (TCF7) has been observed in TNBC. Focus was given to the Wnt pathway receptor, FZD7. To validate its function, inhibition of FZD7 using FZD7shRNA was carried out. Notably decreased cell proliferation, suppressed invasiveness and colony formation in triple negative MDA-MB-231 and BT-20 cells were observed. Mechanism study indicated that these effects occurred through silencing the canonical Wnt signaling pathway, as evidenced by loss of nuclear accumulation of ï?¢-catenin and decreased transcriptional activity of TCF7. In vivo study revealed that FZD7shRNA significantly suppressed the tumor formation in xenotransplation mice due to decrease cell proliferation. Our finding suggests that FZD7 involved canonical Wnt signaling pathway is essential for tumorigenesis of TNBC. Thus, FZD7 may be a biomarker and a potential therapeutic target for triple negative breast cancer. 14 pretreatment non-triple negative breast tumors compare with 5 triple negative breast tumor.
2011-06-01 | E-GEOD-27447 | biostudies-arrayexpress
Project description:Triple-negative breast cancer (TNBC) is an aggressive and highly lethal disease. Because of its heterogeneity and lack of hormone receptors or HER2 expression, targeted therapy is limited. Here, by performing a functional siRNA screening for 2-OG–dependent enzymes, we identified gamma-butyrobetaine hydroxylase 1 (BBOX1) as an essential gene for TNBC tumorigenesis. BBOX1 depletion inhibits TNBC cell growth while not affecting normal breast cells. Mechanistically, BBOX1 binds with the calcium channel inositol-1,4,5-trisphosphate receptor type 3 (IP3R3) in an enzymatic-dependent manner and prevents its ubiquitination and proteasomal degradation. BBOX1 depletion suppresses IP3R3-mediated endoplasmic reticulum calcium release, therefore impairing calcium-dependent energy-generating processes including mitochondrial respiration and mTORC1-mediated glycolysis, which leads to apoptosis and impaired cell-cycle progression in TNBC cells. Therapeutically, genetic depletion or pharmacologic inhibition of BBOX1 inhibits TNBC tumor growth in vitro and in vivo. Our study highlights the importance of targeting the previously uncharacterized BBOX1–IP3R3–calcium oncogenic signaling axis in TNBC.
2020-12-02 | GSE152317 | GEO
Project description:The tumor suppressor menin has dual functions, acting either as a tumor suppressor or as an oncogene/oncoprotein, depending on the oncological context. Triple-negative breast cancer (TNBC) is characterized by lack of expression of the estrogen receptor, progesterone receptor, and human epidermal growth factor receptor 2 and is often a basal-like breast cancer. TNBC is associated with a dismal prognosis and an insufficient response to chemotherapies. Previously, menin was shown to play a proliferative role in ER-positive breast cancer; however, functions of menin in TNBC remains unknown. We have demonstrated that menin is expressed in various TNBC subtypes with the strongest menin expression in the TNBC Hs 578T cells. Depletion of menin by antisense oligonucleotide inhibited cell proliferation, enhanced apoptosis, and induced cell cycle arrest in Hs 578T cells, highlighting oncogenic functions of menin in this TNBC model. To better understand the menin function, we performed AP-MS (Affinity Purification-Mass Spectrometry) using specific antibody against menin. Analysis of menin interactome suggested that menin could drive TNBC tumorigenesis through regulation of the MLL/KMT2A-driven transcriptional activity, mRNA 3’ end processing and apoptosis.
2021-09-10 | PXD024176 | Pride
Project description:<p>In this study the investigators looked at adaptive reprogramming impact on the kinome when a MEK inhibitor called GSK1120212 (trametinib) was administered in a "window of opportunity" trial. GSK1120212 is not yet approved by the FDA for use in breast cancer patients. The investigators gave GSK1120212 for a short period of time (one week) to examine MEK and the other kinase expression in cancer cells both before and after the study drug is given. The investigators gave this drug for research purposes only. The length of time it was given is not intended to treat cancer.</p> <p>Recently researchers at UNC developed a process that can comprehensively profile the majority of the individual kinases in the kinome and examine the impact on kinase expression of kinase inhibitors (Duncan et al, Cell 2012, PMID: 22500798). This can tell us which kinases need to be concurrently blocked to augment responsiveness and prevent acquired resistance so that the investigators can design the best combinations of kinase blocking drugs for triple negative breast cancer. This is especially important for individuals with triple negative breast cancer (TNBC) because there are no targeted drugs available that can block molecules that affect tumor growth. The investigators believe that kinase-blocking drugs have the potential to be a more effective treatment for people with TNBC.</p> <p>In this recently published study (Zawistowski et al, Cancer Discovery 2017, PMID: 28108460), TNBC patients treated with trametinib for 7 days resulted in a transcriptional response characterized by significant reprogramming of the tyrosine kinome, and this adaptive bypass response in human tumors was found to be similar to that seen in preclinical models including TNBC cell lines and mouse xenografts. In this study we also examined whether reprogramming differed between TNBC molecular subtypes, finding that basal-like and claudin-low human TNBC cells and mouse tumor subtypes had different adaptive transcriptional responses to MEK-ERK inhibition. Mechanistically we found that genome-wide enhancer remodeling drove the adaptive transcriptional response, suggesting that epigenetic approaches to reprogramming may be more durable than kinase inhibitor polypharmacology.</p>
| phs001405 | dbGaP
Project description:Triple negative breast cancer (TNBC) is characterized by high proliferation, poor differentiation and a poor prognosis due to high rates of recurrence. Despite lower overall incidence African American (AA) patients suffer from higher breast cancer mortality in part due to the higher proportion of TNBC cases among AA patients compared to European Americans (EA). It was recently shown that the clinical heterogeneity of TNBC is reflected by distinct transcriptional programs with distinct drug response profiles in preclinical models. In this study, we used gene expression profiling and immunohistochemistry to eluicidate potential differences between TNBC tumors of EA and AA patients on a molecular level. WG-DASL experiment of 90 FFPE samples of ER, PR and HER2 (triple) negative breast cancer samples diagnosed between 1987 and 2007. Invasive disease was identified on H&E sections by the study pathologist and one to three 1.5 mm cores were punched from the top down in the designated tumor areas of each FFPE block. The cores were deparaffinized with xylene at 50°C for 3 minutes. RNA was extracted using the RecoverAll Total Nucleic Acid Isolation kit (Applied Biosystems) following the manufacturer's protocol. The isolated RNA was hybridized to Whole-Genome DASL (HumanRef8 V 3.0, Illumina) at the Yale Center for Genome Analysis. 90 primary tumor RNA samples from 90 patients were adequate for analysis and passed Quality control.
2013-08-15 | E-GEOD-46581 | biostudies-arrayexpress
Project description:Triple-negative breast cancer (TNBC) is an aggressive subtype of breast cancer with poor prognosis. The high malignancy of TNBC is contributed by its heterogeneity and enrichment of cancer stem cells. By performing multiomic profiling, we recently uncovered super-enhancer heterogeneity between breast cancer subtypes. Here, we identify TCOF1 as a novel super-enhancer-regulated gene that promotes TNBC growth and stemness. TCOF1, which plays a critical role in craniofacial development, is frequently upregulated in TNBC and its elevated expression correlates with shorter overall survival. Whereas TCOF1 depletion has potent effects on the growth and stemness of basal-like TNBC, it has no effect on mesenchymal-like cells, highlighting the distinct molecular dependency in different subgroups of TNBC. Whole genome RNA sequencing uncovers several stem cell molecules regulated by TCOF1. We further demonstrate that the upregulation of KIT by TCOF1 mediates TNBC stemness. These findings provide a rationale for developing therapeutics targeting TCOF1 in basal-like TNBC.
2021-11-02 | GSE168835 | GEO
Project description:To identify novel molecular targets for triple negative breast cancer (TNBC), we have employed whole genome microarray expression profiling. We purified 30 surgically resected breast cancer tissue diagnosed triple negative by means of immunohistochemical staining and 13 normal mammary ductal cells with lasermicrobeam microdissection system (PALM MicroBeam, Carl Zeiss MicroImaging Co., Ltd), performed whole human genome microarray, and compared gene expression levels of TNBC, normal mammary ductal cells, and normal vital organs to develop molecular targets with a minimum risk. Gene expression levels of 30 TNBC, 13 normal mammary ductal cells, and 4 normal vital tissues were evaluated. to clarify the molecular mechanism involved in TNBC, we analyzed gene expression profiles of 30 TNBC as well as 13 normal epithelial ductal cells purified by laser microbeam microdissection, and identified 301 transcripts that were significantly up-regulated and 321 transcripts that were significantly down-regulated in TNBC. In addition, gene-expression profiles analysis of normal human vital organs including heart, lung, liver, and kidney allowed us to identify 90 cancer-specific genes involved in breast carcinogenesis such as NEK2, PBK, DTL, MELK and GPSM2. Among them, we focused on cell cycle regulators, asp (abnormal spindle) homolog, microcephaly associated (Drosophila) (ASPM) and centromere protein K (CENPK) as novel therapeutic targets for TNBC.
2012-12-21 | E-GEOD-38959 | biostudies-arrayexpress
Project description:Triple negative breast cancer (TNBC) is a heterogeneous and clinically aggressive disease for which there is no targeted therapy. Here we report the preferential and high sensitivity of TNBCs to BET bromodomain inhibitors such as JQ1 manifested by cell cycle arrest in early G1, apoptosis, and induction of markers of luminal epithelial differentiation in vitro and in vivo. The sensitivity of TNBC and other tumor types to BET inhibition establishes a rationale for clinical investigation, and a motivation to understand mechanisms of resistance. After engendering acquired resistance to BET inhibition in previously sensitive TNBCs, we utilized integrative approaches to identify a unique mechanism of epigenomic resistance to this epigenetic therapy. Resistant cells remain dependent on BRD4, confirmed by RNA interference. However, TNBC cells adapt to BET bromodomain inhibition by re-recruitment of unmutated BRD4 to super-enhancers, now in a bromodomain-independent manner. Proteomic studies of resistant TNBC identify hyper-phosphorylation of BRD4 and strong association with MED1. Together, these studies provide a rationale for BET inhibition in TNBC and argue for combination strategies to anticipate clinical drug resistance. ChIP-seq in parental and JQ1 resistant triple negative breast cancer (TNBC) in response to DMSO or JQ1 treatment
2016-01-07 | E-GEOD-63581 | biostudies-arrayexpress
Project description:Triple negative breast cancer (TNBC) is a heterogeneous and clinically aggressive disease for which there is no targeted therapy. Here we report the preferential and high sensitivity of TNBCs to BET bromodomain inhibitors such as JQ1 manifested by cell cycle arrest in early G1, apoptosis, and induction of markers of luminal epithelial differentiation in vitro and in vivo. The sensitivity of TNBC and other tumor types to BET inhibition establishes a rationale for clinical investigation, and a motivation to understand mechanisms of resistance. After engendering acquired resistance to BET inhibition in previously sensitive TNBCs, we utilized integrative approaches to identify a unique mechanism of epigenomic resistance to this epigenetic therapy. Resistant cells remain dependent on BRD4, confirmed by RNA interference. However, TNBC cells adapt to BET bromodomain inhibition by re-recruitment of unmutated BRD4 to super-enhancers, now in a bromodomain-independent manner. Proteomic studies of resistant TNBC identify hyper-phosphorylation of BRD4 and strong association with MED1. Together, these studies provide a rationale for BET inhibition in TNBC and argue for combination strategies to anticipate clinical drug resistance. Chem-Seq in parental and JQ1 resistant triple negative breast cancer (TNBC)
2016-01-07 | E-GEOD-63284 | biostudies-arrayexpress