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MDA-MB-231

RRID:CVCL_0062

Organism

Homo sapiens

Comments

Group: Triple negative breast cancer (TNBC) cell line. Part of: Cancer Cell Line Encyclopedia (CCLE) project. Part of: COSMIC cell lines project. Part of: ENCODE project common cell types; tier 3. Part of: ICBP43 breast cancer cell line panel. Part of: JFCR39 cancer cell line panel. Part of: JFCR45 cancer cell line panel. Part of: KuDOS 95 cell line panel. Part of: MD Anderson Cell Lines Project. Part of: NCI-60 cancer cell line panel. Registration: Chiron Master Culture Collection; CMCC 10583 (CMCC #10583). Doubling time: 1.3 days (PubMed=9671407); 41.9 hours (NCI-DTP); 38 hours (ATCC); ~25-30 hours (DSMZ); ~38 hours (PBCF). HLA typing: A*02:01,02:17; B*40:02,41:01; C*02:02:02,17; DPB1*02:01:02,17:01; DQB1*02:02,03:01:01; DRB1*07:01,13:05 (PubMed=15748285). HLA typing: A*02:17,02:01; B*41:01,40:02; C*17:01,02:02; DQA1*02:01,02:01; DQB1*03:04,03:04; DRB1*13:05,07:01 (PubMed=25960936). Microsatellite instability: Stable (MSS) (PubMed=12661003; Sanger). Sequence variation: Heterozygous for BRAF p.Gly464Val (c.1391G>T) (PubMed=17088437). Sequence variation: Heterozygous for KRAS p.Gly13Asp (c.38G>A) (PubMed=17088437). Sequence variation: Homozygous for TP53 p.Arg280Lys (c.839G>A) (PubMed=16541312; PubMed=17088437; PubMed=18277095; PubMed=28889351). Omics: Array-based CGH. Omics: Cell surface proteome. Omics: CNV analysis. Omics: Deep exome analysis. Omics: Deep proteome analysis. Omics: Deep RNAseq analysis. Omics: DNA methylation analysis. Omics: Fluorescence phenotype profiling. Omics: lncRNA expression profiling. Omics: Metabolome analysis. Omics: miRNA expression profiling. Omics: N-glycan profiling. Omics: Protein expression by reverse-phase protein arrays. Omics: Secretome proteome analysis. Omics: SNP array analysis. Omics: Transcriptome analysis. Misspelling: MDA-MD-231; In Cosmic 1071900 and Cosmic 1176602. Misspelling: MDA-321; In GEO GSM459713. Misspelling: MDA-MG-231; In PubMed=6582512. Misspelling: MD-MB-231; In PRIDE PXD010634. Misspelling: MD-MBA-231; Occasionally. Discontinued: ATCC; CRL-12532. Derived from metastatic site: Pleural effusion.

Proper Citation

ECACC Cat# 92020424, RRID:CVCL_0062

Category

Cancer cell line

Sex

Female

Synonyms

MDA-MB 231, MDA.MB.231, MDA MB 231, MDA MB231, MDA Mb231, MDA-MB231, MDAMB-231, MDAMB231, MDA-231, MDA231, MB231, MD Anderson-Metastatic Breast-231

Vendor

ECACC

Cat Num

92020424

Cross References

BTO; BTO:0000815 CLO; CLO_0007634 EFO; EFO_0001209 MCCL; MCC:0000313 CLDB; cl3402 CLDB; cl3404 CLDB; cl3405 CLDB; cl4945 AddexBio; C0006002/58 ArrayExpress; E-MTAB-2706 ArrayExpress; E-MTAB-2770 ArrayExpress; E-MTAB-3610 ATCC; CRL-12532 ATCC; HTB-26 ATCC; CRM-HTB-26 BCRC; 60425 BCRJ; 0164 BioSample; SAMN03472205 BioSample; SAMN05292460 CCLE; MDAMB231_BREAST CCRID; 3111C0001CCC000014 CCRID; 3131C0001000700104 ChEMBL-Cells; CHEMBL3307960 ChEMBL-Targets; CHEMBL400 CLS; 300275/p536_MDA-MB-231 Cosmic; 687494 Cosmic; 871146 Cosmic; 875878 Cosmic; 877450 Cosmic; 894087 Cosmic; 897423 Cosmic; 904377 Cosmic; 905960 Cosmic; 934536 Cosmic; 944294 Cosmic; 974235 Cosmic; 991324 Cosmic; 997929 Cosmic; 1010924 Cosmic; 1018477 Cosmic; 1027053 Cosmic; 1044226 Cosmic; 1046950 Cosmic; 1047693 Cosmic; 1071900 Cosmic; 1092613 Cosmic; 1136369 Cosmic; 1152528 Cosmic; 1175833 Cosmic; 1176602 Cosmic; 1176636 Cosmic; 1183773 Cosmic; 1219444 Cosmic; 1287926 Cosmic; 1289395 Cosmic; 1305383 Cosmic; 1309003 Cosmic; 1312370 Cosmic; 1434952 Cosmic; 1436032 Cosmic; 1466805 Cosmic; 1477428 Cosmic; 1481426 Cosmic; 1524347 Cosmic; 1571793 Cosmic; 1609458 Cosmic; 1927242 Cosmic; 1945862 Cosmic; 1998455 Cosmic; 2009512 Cosmic; 2036667 Cosmic; 2164997 Cosmic; 2301528 Cosmic; 2318377 Cosmic; 2361355 Cosmic; 2560256 Cosmic-CLP; 905960 DSMZ; ACC-732 ECACC; 92020424 GDSC; 905960 GEO; GSM812 GEO; GSM2124 GEO; GSM50184 GEO; GSM50248 GEO; GSM69194 GEO; GSM155213 GEO; GSM185093 GEO; GSM185094 GEO; GSM274653 GEO; GSM344349 GEO; GSM344399 GEO; GSM350547 GEO; GSM378148 GEO; GSM388213 GEO; GSM459713 GEO; GSM481304 GEO; GSM587393 GEO; GSM587394 GEO; GSM750781 GEO; GSM799321 GEO; GSM799384 GEO; GSM820814 GEO; GSM820815 GEO; GSM820816 GEO; GSM847036 GEO; GSM847401 GEO; GSM844594 GEO; GSM844595 GEO; GSM887295 GEO; GSM888370 GEO; GSM967818 GEO; GSM1008905 GEO; GSM1053716 GEO; GSM1153390 GEO; GSM1172979 GEO; GSM1172889 GEO; GSM1181242 GEO; GSM1181365 GEO; GSM1214569 GEO; GSM1238120 GEO; GSM1374651 GEO; GSM1374652 GEO; GSM1401658 GEO; GSM1613823 GEO; GSM1670080 GEO; GSM1833624 GEO; GSM2095710 GEO; GSM2095711 GEO; GSM2124643 ICLC; HTL99004 IZSLER; BS TCL 223 KCB; KCB 200776YJ KCLB; 30026 LINCS_HMS; 50058 LINCS_LDP; LCL-1461 Lonza; 815 MetaboLights; MTBLS337 NCBI_Iran; C578 NCI-DTP; MDA-MB-231 PRIDE; PXD000239 PRIDE; PXD000397 PRIDE; PXD000691 PRIDE; PXD000914 PRIDE; PXD001553 PRIDE; PXD002192 PRIDE; PXD002649 PRIDE; PXD005942 PRIDE; PXD010634 SKY/M-FISH/CGH; 2815 TOKU-E; 2394 Wikidata; Q17577870

Encoding Growth Factor Identity in the Temporal Dynamics of FOXO3 under the Combinatorial Control of ERK and AKT Kinases.

  • Sampattavanich S
  • Cell Syst
  • 2018 Jun 27

Literature context: MDA-MB-231 ATCC ATCC HTB-26; RRID:CVCL_0062 T47D ATCC ATCC HTB-133; RRID:CV


Abstract:

Extracellular growth factors signal to transcription factors via a limited number of cytoplasmic kinase cascades. It remains unclear how such cascades encode ligand identities and concentrations. In this paper, we use live-cell imaging and statistical modeling to study FOXO3, a transcription factor regulating diverse aspects of cellular physiology that is under combinatorial control. We show that FOXO3 nuclear-to-cytosolic translocation has two temporally distinct phases varying in magnitude with growth factor identity and cell type. These phases comprise synchronous translocation soon after ligand addition followed by an extended back-and-forth shuttling; this shuttling is pulsatile and does not have a characteristic frequency, unlike a simple oscillator. Early and late dynamics are differentially regulated by Akt and ERK and have low mutual information, potentially allowing the two phases to encode different information. In cancer cells in which ERK and Akt are dysregulated by oncogenic mutation, the diversity of states is lower.

Funding information:
  • British Heart Foundation - RG/11/17/29256(United Kingdom)
  • NHLBI NIH HHS - U54 HL127365()
  • NIGMS NIH HHS - P50 GM107618()

Chemistry-First Approach for Nomination of Personalized Treatment in Lung Cancer.

  • McMillan EA
  • Cell
  • 2018 May 3

Literature context: DA-MB-157ATCCHTB24MDA-MB-231ATCCHTB26MDA-MB-436ATCCHTB130MDA-MB-453AT


Abstract:

Diversity in the genetic lesions that cause cancer is extreme. In consequence, a pressing challenge is the development of drugs that target patient-specific disease mechanisms. To address this challenge, we employed a chemistry-first discovery paradigm for de novo identification of druggable targets linked to robust patient selection hypotheses. In particular, a 200,000 compound diversity-oriented chemical library was profiled across a heavily annotated test-bed of >100 cellular models representative of the diverse and characteristic somatic lesions for lung cancer. This approach led to the delineation of 171 chemical-genetic associations, shedding light on the targetability of mechanistic vulnerabilities corresponding to a range of oncogenotypes present in patient populations lacking effective therapy. Chemically addressable addictions to ciliogenesis in TTC21B mutants and GLUT8-dependent serine biosynthesis in KRAS/KEAP1 double mutants are prominent examples. These observations indicate a wealth of actionable opportunities within the complex molecular etiology of cancer.

Funding information:
  • NCI NIH HHS - P50 CA070907()
  • NCI NIH HHS - R35 CA197717()
  • NCI NIH HHS - U01 CA176284()
  • NINDS NIH HHS - R01-NS048090(United States)

Novel RNA-Affinity Proteogenomics Dissects Tumor Heterogeneity for Revealing Personalized Markers in Precision Prognosis of Cancer.

  • Wang L
  • Cell Chem Biol
  • 2018 May 17

Literature context: #HTB-26; RRID:CVCL_0062 293T(female) ATCC Catalog #CRL-


Abstract:

To discriminate the patient subpopulations with different clinical outcomes within each breast cancer (BC) subtype, we introduce a robust, clinical-practical, activity-based proteogenomic method that identifies, in their oncogenically active states, candidate biomarker genes bearing patient-specific transcriptomic/genomic alterations of prognostic value. First, we used the intronic splicing enhancer (ISE) probes to sort ISE-interacting trans-acting protein factors (trans-interactome) directly from a tumor tissue for subsequent mass spectrometry characterization. In the retrospective, proteogenomic analysis of patient datasets, we identified those ISE trans-factor-encoding genes showing interaction-correlated expression patterns (iCEPs) as new BC-subtypic genes. Further, patient-specific co-alterations in mRNA expression of select iCEP genes distinguished high-risk patient subsets/subpopulations from other patients within a single BC subtype. Function analysis further validated a tumor-phenotypic trans-interactome contained the drivers of oncogenic splicing switches, representing the predominant tumor cells in a tissue, from which novel personalized biomarkers were clinically characterized/validated for precise prognostic prediction and subsequent individualized alignment of optimal therapy.

Funding information:
  • NCI NIH HHS - R00 CA160351()
  • NCI NIH HHS - R01 CA179992(United States)
  • NCI NIH HHS - R01 CA211732()
  • NCI NIH HHS - R21 CA223675()

lncRNA Epigenetic Landscape Analysis Identifies EPIC1 as an Oncogenic lncRNA that Interacts with MYC and Promotes Cell-Cycle Progression in Cancer.

  • Wang Z
  • Cancer Cell
  • 2018 Apr 9

Literature context: B-26; RRID:CVCL_0062 MDA-MB-361 (MB361) ATCC Cat# HT


Abstract:

We characterized the epigenetic landscape of genes encoding long noncoding RNAs (lncRNAs) across 6,475 tumors and 455 cancer cell lines. In stark contrast to the CpG island hypermethylation phenotype in cancer, we observed a recurrent hypomethylation of 1,006 lncRNA genes in cancer, including EPIC1 (epigenetically-induced lncRNA1). Overexpression of EPIC1 is associated with poor prognosis in luminal B breast cancer patients and enhances tumor growth in vitro and in vivo. Mechanistically, EPIC1 promotes cell-cycle progression by interacting with MYC through EPIC1's 129-283 nt region. EPIC1 knockdown reduces the occupancy of MYC to its target genes (e.g., CDKN1A, CCNA2, CDC20, and CDC45). MYC depletion abolishes EPIC1's regulation of MYC target and luminal breast cancer tumorigenesis in vitro and in vivo.

Funding information:
  • Intramural NIH HHS - Z01 ES100485(United States)

GPR68 Senses Flow and Is Essential for Vascular Physiology.

  • Xu J
  • Cell
  • 2018 Apr 19

Literature context: 6MDA-MB-231 (Breast, Female)ATCCHTB-26HEK293T (Kidney, Fetal)ATCCCRL-1


Abstract:

Mechanotransduction plays a crucial role in vascular biology. One example of this is the local regulation of vascular resistance via flow-mediated dilation (FMD). Impairment of this process is a hallmark of endothelial dysfunction and a precursor to a wide array of vascular diseases, such as hypertension and atherosclerosis. Yet the molecules responsible for sensing flow (shear stress) within endothelial cells remain largely unknown. We designed a 384-well screening system that applies shear stress on cultured cells. We identified a mechanosensitive cell line that exhibits shear stress-activated calcium transients, screened a focused RNAi library, and identified GPR68 as necessary and sufficient for shear stress responses. GPR68 is expressed in endothelial cells of small-diameter (resistance) arteries. Importantly, Gpr68-deficient mice display markedly impaired acute FMD and chronic flow-mediated outward remodeling in mesenteric arterioles. Therefore, GPR68 is an essential flow sensor in arteriolar endothelium and is a critical signaling component in cardiovascular pathophysiology.

Funding information:
  • NCI NIH HHS - U24 CA126543(United States)

MELK expression correlates with tumor mitotic activity but is not required for cancer growth.

  • Giuliano CJ
  • Elife
  • 2018 Feb 8

Literature context: (RRID:CVCL_0248), MDA-MB-231 (RRID:CVCL_0062) cell lines were grown in DMEM


Abstract:

The Maternal Embryonic Leucine Zipper Kinase (MELK) has been identified as a promising therapeutic target in multiple cancer types. MELK over-expression is associated with aggressive disease, and MELK has been implicated in numerous cancer-related processes, including chemotherapy resistance, stem cell renewal, and tumor growth. Previously, we established that triple-negative breast cancer cell lines harboring CRISPR/Cas9-induced null mutations in MELK proliferate at wild-type levels in vitro (Lin et al., 2017). Here, we generate several additional knockout clones of MELK and demonstrate that across cancer types, cells lacking MELK exhibit wild-type growth in vitro, under environmental stress, in the presence of cytotoxic chemotherapies, and in vivo. By combining our MELK-knockout clones with a recently described, highly specific MELK inhibitor, we further demonstrate that the acute inhibition of MELK results in no specific anti-proliferative phenotype. Analysis of gene expression data from cohorts of cancer patients identifies MELK expression as a correlate of tumor mitotic activity, explaining its association with poor clinical prognosis. In total, our results demonstrate the power of CRISPR/Cas9-based genetic approaches to investigate cancer drug targets, and call into question the rationale for treating patients with anti-MELK monotherapies.

Funding information:
  • NIDDK NIH HHS - R01 DK088718(United States)
  • NIH Office of the Director - 1DP5OD021385()

Loss of functional BAP1 augments sensitivity to TRAIL in cancer cells.

  • Kolluri KK
  • Elife
  • 2018 Jan 18

Literature context: come Trust Sanger Institute, UK RRID:CVCL_0062


Abstract:

Malignant mesothelioma (MM) is poorly responsive to systemic cytotoxic chemotherapy and invariably fatal. Here we describe a screen of 94 drugs in 15 exome-sequenced MM lines and the discovery of a subset defined by loss of function of the nuclear deubiquitinase BRCA associated protein-1 (BAP1) that demonstrate heightened sensitivity to TRAIL (tumour necrosis factor-related apoptosis-inducing ligand). This association is observed across human early passage MM cultures, mouse xenografts and human tumour explants. We demonstrate that BAP1 deubiquitinase activity and its association with ASXL1 to form the Polycomb repressive deubiquitinase complex (PR-DUB) impacts TRAIL sensitivity implicating transcriptional modulation as an underlying mechanism. Death receptor agonists are well-tolerated anti-cancer agents demonstrating limited therapeutic benefit in trials without a targeting biomarker. We identify BAP1 loss-of-function mutations, which are frequent in MM, as a potential genomic stratification tool for TRAIL sensitivity with immediate and actionable therapeutic implications.

Funding information:
  • Cancer Research UK - A17341()
  • NINDS NIH HHS - R01NS043915(United States)
  • Wellcome - WT097452MA()
  • Wellcome Trust - 106555/Z/14/Z()
  • Wellcome Trust - WT107963AIA()

LIPG signaling promotes tumor initiation and metastasis of human basal-like triple-negative breast cancer.

  • Lo PK
  • Elife
  • 2018 Jan 19

Literature context: ll lines, including MDA-MB-231 (RRID:CVCL_0062), MDA-MB-468 (RRID:CVCL_0419),


Abstract:

Current understanding of aggressive human basal-like triple-negative breast cancer (TNBC) remains incomplete. In this study, we show endothelial lipase (LIPG) is aberrantly overexpressed in basal-like TNBCs. We demonstrate that LIPG is required for in vivo tumorigenicity and metastasis of TNBC cells. LIPG possesses a lipase-dependent function that supports cancer cell proliferation and a lipase-independent function that promotes invasiveness, stemness and basal/epithelial-mesenchymal transition features of TNBC. Mechanistically, LIPG executes its oncogenic function through its involvement in interferon-related DTX3L-ISG15 signaling, which regulates protein function and stability by ISGylation. We show that DTX3L, an E3-ubiquitin ligase, is required for maintaining LIPG protein levels in TNBC cells by inhibiting proteasome-mediated LIPG degradation. Inactivation of LIPG impairs DTX3L-ISG15 signaling, indicating the existence of DTX3L-LIPG-ISG15 signaling. We further reveal LIPG-ISG15 signaling is lipase-independent. We demonstrate that DTX3L-LIPG-ISG15 signaling is essential for malignancies of TNBC cells. Targeting this pathway provides a novel strategy for basal-like TNBC therapy.

Cellular Migration Ability Is Modulated by Extracellular Purines in Ovarian Carcinoma SKOV-3 Cells.

  • Martínez-Ramírez AS
  • J. Cell. Biochem.
  • 2018 Jan 2

Literature context: 75/p536_MDA-MB-231, RRID:CVCL_0062) cells. These cellular lines we


Abstract:

Extracellular nucleotides and nucleosides have emerged as important elements regulating tissue homeostasis. Acting through specific receptors, have the ability to control gene expression patterns to direct cellular fate. We observed that SKOV-3 cells express the ectonucleotidases: ectonucleotide pyrophosphatase 1 (ENPP1), ecto-5'-nucleotidase (NT5E), and liver alkaline phosphatase (ALPL). Strikingly, in pulse and chase experiments supplemented with ATP, SKOV-3 cells exhibited low catabolic efficiency in the conversion of ADP into AMP, but they were efficient in converting AMP into adenosine. Since these cells release ATP, we proposed that the conversion of ADP into AMP is a regulatory node associated with the migratory ability and the mesenchymal characteristics shown by SKOV-3 cells under basal conditions. The landscape of gene expression profiles of SKOV-3 cell cultures treated with apyrase or adenosine demonstrated similarities (e.g., decrease FGF16 transcript) and differences (e.g., the negative regulation of Wnt 2, and 10B by adenosine). Thus, in SKOV-3 we analyzed the migratory ability and the expression of epithelium to mesenchymal transition (EMT) markers in response to apyrase. Apyrase-treatment favored the epithelial-like phenotype, as revealed by the re-location of E-cadherin to the cell to cell junctions. Pharmacological approaches strongly suggested that the effect of Apyrase involved the accumulation of extracellular adenosine; this notion was strengthened when the incubation of the SKOV-3 cell with α,β-methylene ADP (CD73 inhibitor) or adenosine deaminase was sufficient to abolish the effect of apyrase on cell migration. Overall, adenosine signaling is a fine tune mechanism in the control of cell phenotype in cancer. J. Cell. Biochem. 118: 4468-4478, 2017. © 2017 Wiley Periodicals, Inc.

Acetyl-CoA Carboxylase 1-Dependent Protein Acetylation Controls Breast Cancer Metastasis and Recurrence.

  • Rios Garcia M
  • Cell Metab.
  • 2017 Dec 5

Literature context: TCCCRL-2539Human: MDA-MB-231ATCCHTB-26Human: MCF-7ATCCHTB-22Human: T47


Abstract:

Breast tumor recurrence and metastasis represent the main causes of cancer-related death in women, and treatments are still lacking. Here, we define the lipogenic enzyme acetyl-CoA carboxylase (ACC) 1 as a key player in breast cancer metastasis. ACC1 phosphorylation was increased in invading cells both in murine and human breast cancer, serving as a point of convergence for leptin and transforming growth factor (TGF) β signaling. ACC1 phosphorylation was mediated by TGFβ-activated kinase (TAK) 1, and ACC1 inhibition was indispensable for the elevation of cellular acetyl-CoA, the subsequent increase in Smad2 transcription factor acetylation and activation, and ultimately epithelial-mesenchymal transition and metastasis induction. ACC1 deficiency worsened tumor recurrence upon primary tumor resection in mice, and ACC1 phosphorylation levels correlated with metastatic potential in breast and lung cancer patients. Given the demonstrated effectiveness of anti-leptin receptor antibody treatment in halting ACC1-dependent tumor invasiveness, our work defines a "metabolocentric" approach in metastatic breast cancer therapy.

Funding information:
  • NIDDK NIH HHS - P30 DK065988(United States)

Pharmacological augmentation of nicotinamide phosphoribosyltransferase (NAMPT) protects against paclitaxel-induced peripheral neuropathy.

  • LoCoco PM
  • Elife
  • 2017 Nov 10

Literature context: -231 ATCC ATCC Cat# CRM-HTB-26; RRID:CVCL_0062 Cell line maintained in A. Risi


Abstract:

Chemotherapy-induced peripheral neuropathy (CIPN) arises from collateral damage to peripheral afferent sensory neurons by anticancer pharmacotherapy, leading to debilitating neuropathic pain. No effective treatment for CIPN exists, short of dose-reduction which worsens cancer prognosis. Here, we report that stimulation of nicotinamide phosphoribosyltransferase (NAMPT) produced robust neuroprotection in an aggressive CIPN model utilizing the frontline anticancer drug, paclitaxel (PTX). Daily treatment of rats with the first-in-class NAMPT stimulator, P7C3-A20, prevented behavioral and histologic indicators of peripheral neuropathy, stimulated tissue NAD recovery, improved general health, and abolished attrition produced by a near maximum-tolerated dose of PTX. Inhibition of NAMPT blocked P7C3-A20-mediated neuroprotection, whereas supplementation with the NAMPT substrate, nicotinamide, potentiated a subthreshold dose of P7C3-A20 to full efficacy. Importantly, P7C3-A20 blocked PTX-induced allodynia in tumored mice without reducing antitumoral efficacy. These findings identify enhancement of NAMPT activity as a promising new therapeutic strategy to protect against anticancer drug-induced peripheral neurotoxicity.

Funding information:
  • NIMH NIH HHS - T32 MH065214(United States)

GLUL Promotes Cell Proliferation in Breast Cancer.

  • Wang Y
  • J. Cell. Biochem.
  • 2017 Nov 2

Literature context: RL-12532, RRID:CVCL_0062), and MCF7


Abstract:

Glutamate-ammonia ligase (GLUL) belongs to the glutamine synthetase family. It catalyzes the synthesis of glutamine from glutamate and ammonia in an ATP-dependent reaction. Here, we found higher expression of GLUL in the breast cancer patients was associated with larger tumor size and higher level of HER2 expression. In addition, GLUL was heterogeneously expressed in various breast cancer cells. The mRNA and protein expression levels of GLUL in SK-BR-3 cells were obviously higher than that in the other types of breast cancer cells. Results showed GLUL knockdown in SK-BR-3 cells could significantly decrease the proliferation ability. Furthermore, GLUL knockdown markedly inhibited the p38 MAPK and ERK1/ERK2 signaling pathways in SK-BR-3 cells. Thus, GLUL may represent a novel target for selectively inhibiting p38 MAPK and ERK1/ERK2 signaling pathways and the proliferation potential of breast cancer cells. J. Cell. Biochem. 118: 2018-2025, 2017. © 2016 Wiley Periodicals, Inc.

Funding information:
  • NEI NIH HHS - R01 EY004067(United States)

ESRP1 Mutations Cause Hearing Loss due to Defects in Alternative Splicing that Disrupt Cochlear Development.

  • Rohacek AM
  • Dev. Cell
  • 2017 Nov 6

Literature context: erN/AHuman: MDA-MB-231 cellsATCCHTB-26Mouse: Esrp1-/- embryonic stem c


Abstract:

Alternative splicing contributes to gene expression dynamics in many tissues, yet its role in auditory development remains unclear. We performed whole-exome sequencing in individuals with sensorineural hearing loss (SNHL) and identified pathogenic mutations in Epithelial Splicing-Regulatory Protein 1 (ESRP1). Patient-derived induced pluripotent stem cells showed alternative splicing defects that were restored upon repair of an ESRP1 mutant allele. To determine how ESRP1 mutations cause hearing loss, we evaluated Esrp1-/- mouse embryos and uncovered alterations in cochlear morphogenesis, auditory hair cell differentiation, and cell fate specification. Transcriptome analysis revealed impaired expression and splicing of genes with essential roles in cochlea development and auditory function. Aberrant splicing of Fgfr2 blocked stria vascularis formation due to erroneous ligand usage, which was corrected by reducing Fgf9 gene dosage. These findings implicate mutations in ESRP1 as a cause of SNHL and demonstrate the complex interplay between alternative splicing, inner ear development, and auditory function.

Funding information:
  • NHGRI NIH HHS - U01 HG006546()
  • NIA NIH HHS - R01 AG046544()
  • NIDCD NIH HHS - F31 DC014647()
  • NIDCD NIH HHS - R01 DC006254()
  • NIDCR NIH HHS - R01 DE024749()
  • NIGMS NIH HHS - T32 GM008216()

Tumor-Suppressor Inactivation of GDF11 Occurs by Precursor Sequestration in Triple-Negative Breast Cancer.

  • Bajikar SS
  • Dev. Cell
  • 2017 Nov 20

Literature context: -26, RRID:CVCL_0062 Human: MDA-MB-436 ATCC Cat #HTB


Abstract:

Triple-negative breast cancer (TNBC) is an aggressive and heterogeneous carcinoma in which various tumor-suppressor genes are lost by mutation, deletion, or silencing. Here we report a tumor-suppressive mode of action for growth-differentiation factor 11 (GDF11) and an unusual mechanism of its inactivation in TNBC. GDF11 promotes an epithelial, anti-invasive phenotype in 3D triple-negative cultures and intraductal xenografts by sustaining expression of E-cadherin and inhibitor of differentiation 2 (ID2). Surprisingly, clinical TNBCs retain the GDF11 locus and expression of the protein itself. GDF11 bioactivity is instead lost because of deficiencies in its convertase, proprotein convertase subtilisin/kexin type 5 (PCSK5), causing inactive GDF11 precursor to accumulate intracellularly. PCSK5 reconstitution mobilizes the latent TNBC reservoir of GDF11 in vitro and suppresses triple-negative mammary cancer metastasis to the lung of syngeneic hosts. Intracellular GDF11 retention adds to the concept of tumor-suppressor inactivation and reveals a cell-biological vulnerability for TNBCs lacking therapeutically actionable mutations.

Funding information:
  • NIDCD NIH HHS - R01 DC011184(United States)

Restoration of Replication Fork Stability in BRCA1- and BRCA2-Deficient Cells by Inactivation of SNF2-Family Fork Remodelers.

  • Taglialatela A
  • Mol. Cell
  • 2017 Oct 19

Literature context: D: RRID:CVCL_0062 MDA-MB-436 ATCC Cat#HTB-130; RR


Abstract:

To ensure the completion of DNA replication and maintenance of genome integrity, DNA repair factors protect stalled replication forks upon replication stress. Previous studies have identified a critical role for the tumor suppressors BRCA1 and BRCA2 in preventing the degradation of nascent DNA by the MRE11 nuclease after replication stress. Here we show that depletion of SMARCAL1, a SNF2-family DNA translocase that remodels stalled forks, restores replication fork stability and reduces the formation of replication stress-induced DNA breaks and chromosomal aberrations in BRCA1/2-deficient cells. In addition to SMARCAL1, other SNF2-family fork remodelers, including ZRANB3 and HLTF, cause nascent DNA degradation and genomic instability in BRCA1/2-deficient cells upon replication stress. Our observations indicate that nascent DNA degradation in BRCA1/2-deficient cells occurs as a consequence of MRE11-dependent nucleolytic processing of reversed forks generated by fork remodelers. These studies provide mechanistic insights into the processes that cause genome instability in BRCA1/2-deficient cells.

Funding information:
  • NCI NIH HHS - R01 CA197774()

A Predictive Model for Selective Targeting of the Warburg Effect through GAPDH Inhibition with a Natural Product.

  • Liberti MV
  • Cell Metab.
  • 2017 Oct 3

Literature context: TB-20Human: MDA-MB-231 cellsATCCHTB-26Experimental Models: Organisms/S


Abstract:

Targeted cancer therapies that use genetics are successful, but principles for selectively targeting tumor metabolism that is also dependent on the environment remain unknown. We now show that differences in rate-controlling enzymes during the Warburg effect (WE), the most prominent hallmark of cancer cell metabolism, can be used to predict a response to targeting glucose metabolism. We establish a natural product, koningic acid (KA), to be a selective inhibitor of GAPDH, an enzyme we characterize to have differential control properties over metabolism during the WE. With machine learning and integrated pharmacogenomics and metabolomics, we demonstrate that KA efficacy is not determined by the status of individual genes, but by the quantitative extent of the WE, leading to a therapeutic window in vivo. Thus, the basis of targeting the WE can be encoded by molecular principles that extend beyond the status of individual genes.

Funding information:
  • NCI NIH HHS - R00 CA168997()
  • NCI NIH HHS - R01 CA174643()
  • NCI NIH HHS - R01 CA193256()
  • NIDDK NIH HHS - R01 DK105550()
  • NIGMS NIH HHS - T32 GM007273()
  • NIGMS NIH HHS - T32 GM008500()

A Peptide Encoded by a Putative lncRNA HOXB-AS3 Suppresses Colon Cancer Growth.

  • Huang JZ
  • Mol. Cell
  • 2017 Oct 5

Literature context: HTB-26; RRID:CVCL_0062 Human: SK-OV-3 ATCC Cat#HTB-77;


Abstract:

A substantial fraction of eukaryotic transcripts are considered long non-coding RNAs (lncRNAs), which regulate various hallmarks of cancer. Here, we discovered that the lncRNA HOXB-AS3 encodes a conserved 53-aa peptide. The HOXB-AS3 peptide, not lncRNA, suppresses colon cancer (CRC) growth. Mechanistically, the HOXB-AS3 peptide competitively binds to the ariginine residues in RGG motif of hnRNP A1 and antagonizes the hnRNP A1-mediated regulation of pyruvate kinase M (PKM) splicing by blocking the binding of the ariginine residues in RGG motif of hnRNP A1 to the sequences flanking PKM exon 9, ensuring the formation of lower PKM2 and suppressing glucose metabolism reprogramming. CRC patients with low levels of HOXB-AS3 peptide have poorer prognoses. Our study indicates that the loss of HOXB-AS3 peptide is a critical oncogenic event in CRC metabolic reprogramming. Our findings uncover a complex regulatory mechanism of cancer metabolism reprogramming orchestrated by a peptide encoded by an lncRNA.

Tumour-derived PGD2 and NKp30-B7H6 engagement drives an immunosuppressive ILC2-MDSC axis.

  • Trabanelli S
  • Nat Commun
  • 2017 Sep 19

Literature context: rland), breast (MDA-MB-231, cn: CRM-HTB-26, ATCC), ovarian (HeLa, cn: CCL-


Abstract:

Group 2 innate lymphoid cells (ILC2s) are involved in human diseases, such as allergy, atopic dermatitis and nasal polyposis, but their function in human cancer remains unclear. Here we show that, in acute promyelocytic leukaemia (APL), ILC2s are increased and hyper-activated through the interaction of CRTH2 and NKp30 with elevated tumour-derived PGD2 and B7H6, respectively. ILC2s, in turn, activate monocytic myeloid-derived suppressor cells (M-MDSCs) via IL-13 secretion. Upon treating APL with all-trans retinoic acid and achieving complete remission, the levels of PGD2, NKp30, ILC2s, IL-13 and M-MDSCs are restored. Similarly, disruption of this tumour immunosuppressive axis by specifically blocking PGD2, IL-13 and NKp30 partially restores ILC2 and M-MDSC levels and results in increased survival. Thus, using APL as a model, we uncover a tolerogenic pathway that may represent a relevant immunosuppressive, therapeutic targetable, mechanism operating in various human tumour types, as supported by our observations in prostate cancer.Group 2 innate lymphoid cells (ILC2s) modulate inflammatory and allergic responses, but their function in cancer immunity is still unclear. Here the authors show that, in acute promyelocytic leukaemia, tumour-activated ILC2s secrete IL-13 to induce myeloid-derived suppressor cells and support tumour growth.

Focal Adhesion- and IGF1R-Dependent Survival and Migratory Pathways Mediate Tumor Resistance to mTORC1/2 Inhibition.

  • Yoon SO
  • Mol. Cell
  • 2017 Aug 3

Literature context: Models: Cell LinesMDA-MB-231ATCCHTB-26AU565ATCCCRL-2351MDA-MB-468ATCCH


Abstract:

Aberrant signaling by the mammalian target of rapamycin (mTOR) contributes to the devastating features of cancer cells. Thus, mTOR is a critical therapeutic target and catalytic inhibitors are being investigated as anti-cancer drugs. Although mTOR inhibitors initially block cell proliferation, cell viability and migration in some cancer cells are quickly restored. Despite sustained inhibition of mTORC1/2 signaling, Akt, a kinase regulating cell survival and migration, regains phosphorylation at its regulatory sites. Mechanistically, mTORC1/2 inhibition promotes reorganization of integrin/focal adhesion kinase-mediated adhesomes, induction of IGFR/IR-dependent PI3K activation, and Akt phosphorylation via an integrin/FAK/IGFR-dependent process. This resistance mechanism contributes to xenograft tumor cell growth, which is prevented with mTOR plus IGFR inhibitors, supporting this combination as a therapeutic approach for cancers.

Ccdc3: A New P63 Target Involved in Regulation Of Liver Lipid Metabolism.

  • Liao W
  • Sci Rep
  • 2017 Aug 21

Literature context: 7 (RRID:CVCL_0031), MDA-MB-231 (RRID:CVCL_0062), human embryonic fibroblast WI


Abstract:

TAp63, a member of the p53 family, has been shown to regulate energy metabolism. Here, we report coiled coil domain-containing 3 (CCDC3) as a new TAp63 target. TAp63, but not ΔNp63, p53 or p73, upregulates CCDC3 expression by directly binding to its enhancer region. The CCDC3 expression is markedly reduced in TAp63-null mouse embryonic fibroblasts and brown adipose tissues and by tumor necrosis factor alpha that reduces p63 transcriptional activity, but induced by metformin, an anti-diabetic drug that activates p63. Also, the expression of CCDC3 is positively correlated with TAp63 levels, but conversely with ΔNp63 levels, during adipocyte differentiation. Interestingly, CCDC3, as a secreted protein, targets liver cancer cells and increases long chain polyunsaturated fatty acids, but decreases ceramide in the cells. CCDC3 alleviates glucose intolerance, insulin resistance and steatosis formation in transgenic CCDC3 mice on high-fat diet (HFD) by reducing the expression of hepatic PPARγ and its target gene CIDEA as well as other genes involved in de novo lipogenesis. Similar results are reproduced by hepatic expression of ectopic CCDC3 in mice on HFD. Altogether, these results demonstrate that CCDC3 modulates liver lipid metabolism by inhibiting liver de novo lipogenesis as a downstream player of the p63 network.

Negative regulation of urokinase receptor activity by a GPI-specific phospholipase C in breast cancer cells.

  • van Veen M
  • Elife
  • 2017 Aug 29

Literature context: e Identifiers: MDA-MB-231 cells RRID:CVCL_0062; Hs578T cells RRID:CVCL_0332; A


Abstract:

The urokinase receptor (uPAR) is a glycosylphosphatidylinositol (GPI)-anchored protein that promotes tissue remodeling, tumor cell adhesion, migration and invasion. uPAR mediates degradation of the extracellular matrix through protease recruitment and enhances cell adhesion, migration and signaling through vitronectin binding and interactions with integrins. Full-length uPAR is released from the cell surface, but the mechanism and significance of uPAR shedding remain obscure. Here we identify transmembrane glycerophosphodiesterase GDE3 as a GPI-specific phospholipase C that cleaves and releases uPAR with consequent loss of function, whereas its homologue GDE2 fails to attack uPAR. GDE3 overexpression depletes uPAR from distinct basolateral membrane domains in breast cancer cells, resulting in a less transformed phenotype, it slows tumor growth in a xenograft model and correlates with prolonged survival in patients. Our results establish GDE3 as a negative regulator of the uPAR signaling network and, furthermore, highlight GPI-anchor hydrolysis as a cell-intrinsic mechanism to alter cell behavior.

Environmental cystine drives glutamine anaplerosis and sensitizes cancer cells to glutaminase inhibition.

  • Muir A
  • Elife
  • 2017 Aug 15

Literature context: ID:CVCL_0062; PC3: ATCC Cat# CRL-1435, RRID:


Abstract:

Many mammalian cancer cell lines depend on glutamine as a major tri-carboxylic acid (TCA) cycle anaplerotic substrate to support proliferation. However, some cell lines that depend on glutamine anaplerosis in culture rely less on glutamine catabolism to proliferate in vivo. We sought to understand the environmental differences that cause differential dependence on glutamine for anaplerosis. We find that cells cultured in adult bovine serum, which better reflects nutrients available to cells in vivo, exhibit decreased glutamine catabolism and reduced reliance on glutamine anaplerosis compared to cells cultured in standard tissue culture conditions. We find that levels of a single nutrient, cystine, accounts for the differential dependence on glutamine in these different environmental contexts. Further, we show that cystine levels dictate glutamine dependence via the cystine/glutamate antiporter xCT/SLC7A11. Thus, xCT/SLC7A11 expression, in conjunction with environmental cystine, is necessary and sufficient to increase glutamine catabolism, defining important determinants of glutamine anaplerosis and glutaminase dependence in cancer.

IGF2 mRNA binding protein-2 is a tumor promoter that drives cancer proliferation through its client mRNAs IGF2 and HMGA1.

  • Dai N
  • Elife
  • 2017 Jul 28

Literature context: Hela (RRID:CVCL_0058), MB-231 (RRID:CVCL_0062), Hep3b (RRID:CVCL_0326) and 29


Abstract:

The gene encoding the Insulin-like Growth Factor 2 mRNA binding protein 2/IMP2 is amplified and overexpressed in many human cancers, accompanied by a poorer prognosis. Mice lacking IMP2 exhibit a longer lifespan and a reduced tumor burden at old age. Herein we show in a diverse array of human cancer cells that IMP2 overexpression stimulates and IMP2 elimination diminishes proliferation by 50-80%. In addition to its known ability to promote the abundance of Insulin-like Growth Factor 2/IGF2, we find that IMP2 strongly promotes IGF action, by binding and stabilizing the mRNA encoding the DNA binding protein HMGA1, a known oncogene. HMGA1 suppresses the abundance of IGF binding protein 2/IGFBP2 and Grb14, inhibitors of IGF action. IMP2 stabilization of HMGA1 mRNA plus IMP2 stimulated IGF2 production synergistically drive cancer cell proliferation and account for IMP2's tumor promoting action. IMP2's ability to promote proliferation and IGF action requires IMP2 phosphorylation by mTOR.

Funding information:
  • NHLBI NIH HHS - 01HL118386(United States)
  • NIDDK NIH HHS - P30 DK040561()
  • NIDDK NIH HHS - P30 DK043351()
  • NIDDK NIH HHS - P30 DK057521()
  • NIDDK NIH HHS - R37 DK017776()

Amplification of F-Actin Disassembly and Cellular Repulsion by Growth Factor Signaling.

  • Yoon J
  • Dev. Cell
  • 2017 Jul 24

Literature context: 0Experimental Models: Cell LinesHuman: MDA-MB-231 cellsATCCHTB-26Human: MCF-7 cellsATCCHTB-22Huma


Abstract:

Extracellular cues that regulate cellular shape, motility, and navigation are generally classified as growth promoting (i.e., growth factors/chemoattractants and attractive guidance cues) or growth preventing (i.e., repellents and inhibitors). Yet, these designations are often based on complex assays and undefined signaling pathways and thus may misrepresent direct roles of specific cues. Here, we find that a recognized growth-promoting signaling pathway amplifies the F-actin disassembly and repulsive effects of a growth-preventing pathway. Focusing on Semaphorin/Plexin repulsion, we identified an interaction between the F-actin-disassembly enzyme Mical and the Abl tyrosine kinase. Biochemical assays revealed Abl phosphorylates Mical to directly amplify Mical Redox-mediated F-actin disassembly. Genetic assays revealed that Abl allows growth factors and Semaphorin/Plexin repellents to combinatorially increase Mical-mediated F-actin disassembly, cellular remodeling, and repulsive axon guidance. Similar roles for Mical in growth factor/Abl-related cancer cell behaviors further revealed contexts in which characterized positive effectors of growth/guidance stimulate such negative cellular effects as F-actin disassembly/repulsion.

Funding information:
  • NIMH NIH HHS - R01 MH085923()

Synergistic interactions with PI3K inhibition that induce apoptosis.

  • Zwang Y
  • Elife
  • 2017 May 31

Literature context: A-MB-231 (RRID:CVCL_0062), CAL-120


Abstract:

Activating mutations involving the PI3K pathway occur frequently in human cancers. However, PI3K inhibitors primarily induce cell cycle arrest, leaving a significant reservoir of tumor cells that may acquire or exhibit resistance. We searched for genes that are required for the survival of PI3K mutant cancer cells in the presence of PI3K inhibition by conducting a genome scale shRNA-based apoptosis screen in a PIK3CA mutant human breast cancer cell. We identified 5 genes (PIM2, ZAK, TACC1, ZFR, ZNF565) whose suppression induced cell death upon PI3K inhibition. We showed that small molecule inhibitors of the PIM2 and ZAK kinases synergize with PI3K inhibition. In addition, using a microscale implementable device to deliver either siRNAs or small molecule inhibitors in vivo, we showed that suppressing these 5 genes with PI3K inhibition induced tumor regression. These observations identify targets whose inhibition synergizes with PI3K inhibitors and nominate potential combination therapies involving PI3K inhibition.

Funding information:
  • NCI NIH HHS - R01 CA130988()
  • NCI NIH HHS - R21 CA177391()
  • NCI NIH HHS - U01 CA176058()

Phosphoglycerate Kinase 1 Phosphorylates Beclin1 to Induce Autophagy.

  • Qian X
  • Mol. Cell
  • 2017 Mar 2

Literature context: Cat# CRL-1687MDA-MB-231ATCCCat# HTB-26U251SigmaCat# 09063001Experiment


Abstract:

Autophagy is crucial for maintaining cell homeostasis. However, the precise mechanism underlying autophagy initiation remains to be defined. Here, we demonstrate that glutamine deprivation and hypoxia result in inhibition of mTOR-mediated acetyl-transferase ARD1 S228 phosphorylation, leading to ARD1-dependent phosphoglycerate kinase 1 (PGK1) K388 acetylation and subsequent PGK1-mediated Beclin1 S30 phosphorylation. This phosphorylation enhances ATG14L-associated class III phosphatidylinositol 3-kinase VPS34 activity by increasing the binding of phosphatidylinositol to VPS34. ARD1-dependent PGK1 acetylation and PGK1-mediated Beclin1 S30 phosphorylation are required for glutamine deprivation- and hypoxia-induced autophagy and brain tumorigenesis. Furthermore, PGK1 K388 acetylation levels correlate with Beclin1 S30 phosphorylation levels and poor prognosis in glioblastoma patients. Our study unearths an important mechanism underlying cellular-stress-induced autophagy initiation in which the protein kinase activity of the metabolic enzyme PGK1 plays an instrumental role and reveals the significance of the mutual regulation of autophagy and cell metabolism in maintaining cell homeostasis.

Funding information:
  • NCI NIH HHS - P30 CA016672()
  • NCI NIH HHS - P50 CA127001()
  • NCI NIH HHS - R01 CA109035()
  • NCI NIH HHS - R01 CA169603()
  • NINDS NIH HHS - R01 NS089754()

Multivalent Small-Molecule Pan-RAS Inhibitors.

  • Welsch ME
  • Cell
  • 2017 Feb 23

Literature context: o. 230132MDA-MB-231ATCCCat. No. HTB-26Experimental Models: Organisms/S


Abstract:

Design of small molecules that disrupt protein-protein interactions, including the interaction of RAS proteins and their effectors, may provide chemical probes and therapeutic agents. We describe here the synthesis and testing of potential small-molecule pan-RAS ligands, which were designed to interact with adjacent sites on the surface of oncogenic KRAS. One compound, termed 3144, was found to bind to RAS proteins using microscale thermophoresis, nuclear magnetic resonance spectroscopy, and isothermal titration calorimetry and to exhibit lethality in cells partially dependent on expression of RAS proteins. This compound was metabolically stable in liver microsomes and displayed anti-tumor activity in xenograft mouse cancer models. These findings suggest that pan-RAS inhibition may be an effective therapeutic strategy for some cancers and that structure-based design of small molecules targeting multiple adjacent sites to create multivalent inhibitors may be effective for some proteins.

Funding information:
  • NCI NIH HHS - R01 CA097061()
  • NCI NIH HHS - R01 CA161061()
  • NCRR NIH HHS - S10 RR025431()
  • NIGMS NIH HHS - P41 GM111244()
  • NIGMS NIH HHS - R01 GM085081()
  • NIGMS NIH HHS - T32 GM008281()
  • NIH HHS - S10 OD012018()

TGF-β reduces DNA ds-break repair mechanisms to heighten genetic diversity and adaptability of CD44+/CD24- cancer cells.

  • Pal D
  • Elife
  • 2017 Jan 16

Literature context: 31 (RRID:CVCL_0062), MDA-MB-4


Abstract:

Many lines of evidence have indicated that both genetic and non-genetic determinants can contribute to intra-tumor heterogeneity and influence cancer outcomes. Among the best described sub-population of cancer cells generated by non-genetic mechanisms are cells characterized by a CD44+/CD24- cell surface marker profile. Here, we report that human CD44+/CD24- cancer cells are genetically highly unstable because of intrinsic defects in their DNA-repair capabilities. In fact, in CD44+/CD24- cells, constitutive activation of the TGF-beta axis was both necessary and sufficient to reduce the expression of genes that are crucial in coordinating DNA damage repair mechanisms. Consequently, we observed that cancer cells that reside in a CD44+/CD24- state are characterized by increased accumulation of DNA copy number alterations, greater genetic diversity and improved adaptability to drug treatment. Together, these data suggest that the transition into a CD44+/CD24- cell state can promote intra-tumor genetic heterogeneity, spur tumor evolution and increase tumor fitness.

Funding information:
  • NCI NIH HHS - P01 CA129243()
  • NCI NIH HHS - P30 CA045508()

TP53 drives invasion through expression of its Δ133p53β variant.

  • Gadea G
  • Elife
  • 2016 Sep 15

Literature context: 1 (RRID:CVCL-0062), MCF7 (RR


Abstract:

TP53 is conventionally thought to prevent cancer formation and progression to metastasis, while mutant TP53 has transforming activities. However, in the clinic, TP53 mutation status does not accurately predict cancer progression. Here we report, based on clinical analysis corroborated with experimental data, that the p53 isoform Δ133p53β promotes cancer cell invasion, regardless of TP53 mutation status. Δ133p53β increases risk of cancer recurrence and death in breast cancer patients. Furthermore Δ133p53β is critical to define invasiveness in a panel of breast and colon cell lines, expressing WT or mutant TP53. Endogenous mutant Δ133p53β depletion prevents invasiveness without affecting mutant full-length p53 protein expression. Mechanistically WT and mutant Δ133p53β induces EMT. Our findings provide explanations to 2 long-lasting and important clinical conundrums: how WT TP53 can promote cancer cell invasion and reciprocally why mutant TP53 gene does not systematically induce cancer progression.