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Homo sapiens


Part of: ICBP43 breast cancer cell line panel. Part of: MD Anderson Cell Lines Project. HLA typing: A*33:01,01:01; B*55:01,40:01; C*07:02,03:03; DQA1*03:02,02:01; DQB1*03:05,03:05; DRB1*04:02,11:44 (PubMed=25960936). Microsatellite instability: Stable (MSS) (PubMed=12661003). Omics: CNV analysis. Omics: Deep proteome analysis. Omics: Deep RNAseq analysis. Omics: DNA methylation analysis. Omics: Glycoproteome analysis by proteomics. Omics: Metabolome analysis. Omics: N-glycan profiling. Omics: Protein expression by reverse-phase protein arrays. Omics: SNP array analysis. Omics: Transcriptome analysis.

Proper Citation

ATCC Cat# CRL-10317, RRID:CVCL_0598


Spontaneously immortalized cell line




MCF 10A, MCF.10A, MCF10A, MCF10a, MCF-10 Attached, Michigan Cancer Foundation-10A



Cat Num


Cross References

BTO; BTO:0001939 CLO; CLO_0007599 EFO; EFO_0001200 MCCL; MCC:0000305 AddexBio; C0006015/4976 ArrayExpress; E-MTAB-2706 ATCC; CRL-10317 BCRJ; 0161 BioSample; SAMN03471375 CCRID; 3131C0001000200025 ChEMBL-Cells; CHEMBL3307364 ChEMBL-Targets; CHEMBL614321 Cosmic; 1136376 Cosmic; 1176649 Cosmic; 2318371 Cosmic; 2560254 ENCODE; ENCBS066ENC ENCODE; ENCBS067ENC ENCODE; ENCBS617ENC ENCODE; ENCBS618ENC ENCODE; ENCBS619ENC ENCODE; ENCBS620ENC ENCODE; ENCBS621ENC ENCODE; ENCBS622ENC ENCODE; ENCBS623ENC GEO; GSM155217 GEO; GSM320171 GEO; GSM350543 GEO; GSM498022 GEO; GSM498026 GEO; GSM756371 GEO; GSM845395 GEO; GSM844584 GEO; GSM1053724 GEO; GSM1172973 GEO; GSM1172882 GEO; GSM1238116 GEO; GSM1328939 GEO; GSM1328940 GEO; GSM1328941 IGRhCellID; MCF10A IZSLER; BS CL 174 KCB; KCB 2014066YJ LINCS_HMS; 50583 LINCS_LDP; LCL-2085 Lonza; 131 MetaboLights; MTBLS401 MetaboLights; MTBLS669 NCBI_Iran; C609 PRIDE; PXD000309 PRIDE; PXD000593 PRIDE; PXD000691 PRIDE; PXD003370 PRIDE; PXD005339 PRIDE; PXD009668 TOKU-E; 2378 Wikidata; Q54904280


CVCL_3633 ! MCF-10F

Bi-allelic Loss of CDKN2A Initiates Melanoma Invasion via BRN2 Activation.

  • Zeng H
  • Cancer Cell
  • 2018 Jul 9

Literature context: L-1619293TATCCCRL-3216MCF10AATCCCRL10317Experimental Models: Organisms/S


Loss of the CDKN2A tumor suppressor is associated with melanoma metastasis, but the mechanisms connecting the phenomena are unknown. Using CRISPR-Cas9 to engineer a cellular model of melanoma initiation from primary human melanocytes, we discovered that a lineage-restricted transcription factor, BRN2, is downstream of CDKN2A and directly regulated by E2F1. In a cohort of melanocytic tumors that capture distinct progression stages, we observed that CDKN2A loss coincides with both the onset of invasive behavior and increased BRN2 expression. Loss of the CDKN2A protein product p16INK4A permitted metastatic dissemination of human melanoma lines in mice, a phenotype rescued by inhibition of BRN2. These results demonstrate a mechanism by which CDKN2A suppresses the initiation of melanoma invasion through inhibition of BRN2.

Funding information:
  • NIAMS NIH HHS - N01-AR-1-2256(United States)

Stochastic Endogenous Replication Stress Causes ATR-Triggered Fluctuations in CDK2 Activity that Dynamically Adjust Global DNA Synthesis Rates.

  • Daigh LH
  • Cell Syst
  • 2018 Jun 4

Literature context: : MCF-10A ATCC ATCC #CRL-10317, RRID:CVCL_0598 Human: BJ-5ta ATCC ATCC #CRL-40


Faithful DNA replication is challenged by stalling of replication forks during S phase. Replication stress is further increased in cancer cells or in response to genotoxic insults. Using live single-cell image analysis, we found that CDK2 activity fluctuates throughout an unperturbed S phase. We show that CDK2 fluctuations result from transient ATR signals triggered by stochastic replication stress events. In turn, fluctuating endogenous CDK2 activity causes corresponding decreases and increases in DNA synthesis rates, linking changes in stochastic replication stress to fluctuating global DNA replication rates throughout S phase. Moreover, cells that re-enter the cell cycle after mitogen stimulation have increased CDK2 fluctuations and prolonged S phase resulting from increased replication stress-induced CDK2 suppression. Thus, our study reveals a dynamic control principle for DNA replication whereby CDK2 activity is suppressed and fluctuates throughout S phase to continually adjust global DNA synthesis rates in response to recurring stochastic replication stress events.

Funding information:
  • Wellcome Trust - (United Kingdom)

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: D:RRID:CVCL_0598 HCC1806 ATCC ATCC CRL-2335; RRI


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()

Co-polymers of Actin and Tropomyosin Account for a Major Fraction of the Human Actin Cytoskeleton.

  • Meiring JCM
  • Curr. Biol.
  • 2018 Jun 22

Literature context: MCF-10A [53] RRID:CVCL_0598 BJpar [10] RRID:CVCL_3653


Tropomyosin proteins form stable coiled-coil dimers that polymerize along the α-helical groove of actin filaments [1]. The actin cytoskeleton consists of both co-polymers of actin and tropomyosin and polymers of tropomyosin-free actin [2]. The fundamental distinction between these two types of filaments is that tropomyosin determines the functional capability of actin filaments in an isoform-dependent manner [3-9]. However, it is unknown what portion of actin filaments are associated with tropomyosin. To address this deficit, we have measured the relative distribution between these two filament populations by quantifying tropomyosin and actin levels in a variety of human cell types, including bone (U2OS); breast epithelial (MCF-10A); transformed breast epithelial (MCF-7); and primary (BJpar), immortalized (BJeH), and Ras-transformed (BJeLR) BJ fibroblasts [10]. Our measurements of tropomyosin and actin predict the saturation of the actin cytoskeleton, implying that tropomyosin binding must be inhibited in order to generate tropomyosin-free actin filaments. We find the majority of actin filaments to be associated with tropomyosin in four of the six cell lines tested and the portion of actin filaments associated with tropomyosin to decrease with transformation. We also discover that high-molecular-weight (HMW), unlike low-molecular-weight (LMW), tropomyosin isoforms are primarily co-polymerized with actin in untransformed cells. This differential partitioning of tropomyosins is not due to a lack of N-terminal acetylation of LMW tropomyosins, but it is, in part, explained by the susceptibility of soluble HMW tropomyosins to proteasomal degradation. We conclude that actin-tropomyosin co-polymers make up a major fraction of the human actin cytoskeleton.

Funding information:
  • Medical Research Council - G1000213(United Kingdom)

Transient external force induces phenotypic reversion of malignant epithelial structures via nitric oxide signaling.

  • Ricca BL
  • Elife
  • 2018 Mar 21

Literature context: ulture of non-malignant MCF10A (RRID:CVCL_0598) and malignant MCF10A-CA1d cell


Non-malignant breast epithelial cells cultured in three-dimensional laminin-rich extracellular matrix (lrECM) form well organized, growth-arrested acini, whereas malignant cells form continuously growing disorganized structures. While the mechanical properties of the microenvironment have been shown to contribute to formation of tissue-specific architecture, how transient external force influences this behavior remains largely unexplored. Here, we show that brief transient compression applied to single malignant breast cells in lrECM stimulated them to form acinar-like structures, a phenomenon we term 'mechanical reversion.' This is analogous to previously described phenotypic 'reversion' using biochemical inhibitors of oncogenic pathways. Compression stimulated nitric oxide production by malignant cells. Inhibition of nitric oxide production blocked mechanical reversion. Compression also restored coherent rotation in malignant cells, a behavior that is essential for acinus formation. We propose that external forces applied to single malignant cells restore cell-lrECM engagement and signaling lost in malignancy, allowing them to reestablish normal-like tissue architecture.

Funding information:
  • National Cancer Institute - PS-OC 60467763-112063-E()
  • National Institute of General Medical Sciences - F32 GM101911()
  • National Science Foundation - CMMI-1235569()
  • NIDDK NIH HHS - R01 DK068443-03(United States)
  • NIGMS NIH HHS - F32 GM101911()

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

  • Giuliano CJ
  • Elife
  • 2018 Feb 8

Literature context: illin and streptomycin. MCF10A (RRID:CVCL_0598) cells were grown in Mammary Ep


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()

p53 orchestrates DNA replication restart homeostasis by suppressing mutagenic RAD52 and POLθ pathways.

  • Roy S
  • Elife
  • 2018 Jan 15

Literature context: ) MCF10a Invitrogen HD PAR-024, RRID:CVCL_0598 Cell line (human) MCF10a p53 nu


Classically, p53 tumor suppressor acts in transcription, apoptosis, and cell cycle arrest. Yet, replication-mediated genomic instability is integral to oncogenesis, and p53 mutations promote tumor progression and drug-resistance. By delineating human and murine separation-of-function p53 alleles, we find that p53 null and gain-of-function (GOF) mutations exhibit defects in restart of stalled or damaged DNA replication forks that drive genomic instability, which isgenetically separable from transcription activation. By assaying protein-DNA fork interactions in single cells, we unveil a p53-MLL3-enabled recruitment of MRE11 DNA replication restart nuclease. Importantly, p53 defects or depletion unexpectedly allow mutagenic RAD52 and POLθ pathways to hijack stalled forks, which we find reflected in p53 defective breast-cancer patient COSMIC mutational signatures. These data uncover p53 as a keystone regulator of replication homeostasis within a DNA restart network. Mechanistically, this has important implications for development of resistance in cancer therapy. Combined, these results define an unexpected role for p53-mediated suppression of replication genome instability.

Funding information:
  • NIAID NIH HHS - R01 AI038382(United States)

Engineered Tissue Folding by Mechanical Compaction of the Mesenchyme.

  • Hughes AJ
  • Dev. Cell
  • 2018 Jan 22

Literature context: al., 2012) ATCC Cat#CRL-10317; RRID:CVCL_0598 Human: MCF10AT cells (MCCs) (Li


Many tissues fold into complex shapes during development. Controlling this process in vitro would represent an important advance for tissue engineering. We use embryonic tissue explants, finite element modeling, and 3D cell-patterning techniques to show that mechanical compaction of the extracellular matrix during mesenchymal condensation is sufficient to drive tissue folding along programmed trajectories. The process requires cell contractility, generates strains at tissue interfaces, and causes patterns of collagen alignment around and between condensates. Aligned collagen fibers support elevated tensions that promote the folding of interfaces along paths that can be predicted by modeling. We demonstrate the robustness and versatility of this strategy for sculpting tissue interfaces by directing the morphogenesis of a variety of folded tissue forms from patterns of mesenchymal condensates. These studies provide insight into the active mechanical properties of the embryonic mesenchyme and establish engineering strategies for more robustly directing tissue morphogenesis ex vivo.

Funding information:
  • Cancer Research UK - 11008(United Kingdom)
  • NICHD NIH HHS - DP2 HD080351()
  • NIDCR NIH HHS - R01 DE016402()
  • NIDCR NIH HHS - R01 DE025668()
  • NIH HHS - S10 OD021664()

JAK/STAT3-Regulated Fatty Acid β-Oxidation Is Critical for Breast Cancer Stem Cell Self-Renewal and Chemoresistance.

  • Wang T
  • Cell Metab.
  • 2018 Jan 9

Literature context: tal Models: Cell LinesMCF10AATCCCRL-10317MCF-7ATCCHTB-22MDA-MB-468ATCCHTB


Cancer stem cells (CSCs) are critical for cancer progression and chemoresistance. How lipid metabolism regulates CSCs and chemoresistance remains elusive. Here, we demonstrate that JAK/STAT3 regulates lipid metabolism, which promotes breast CSCs (BCSCs) and cancer chemoresistance. Inhibiting JAK/STAT3 blocks BCSC self-renewal and expression of diverse lipid metabolic genes, including carnitine palmitoyltransferase 1B (CPT1B), which encodes the critical enzyme for fatty acid β-oxidation (FAO). Moreover, mammary-adipocyte-derived leptin upregulates STAT3-induced CPT1B expression and FAO activity in BCSCs. Human breast-cancer-derived data suggest that the STAT3-CPT1B-FAO pathway promotes cancer cell stemness and chemoresistance. Blocking FAO and/or leptin re-sensitizes them to chemotherapy and inhibits BCSCs in mouse breast tumors in vivo. We identify a critical pathway for BCSC maintenance and breast cancer chemoresistance.

Funding information:
  • NCI NIH HHS - P30 CA033572()
  • NCI NIH HHS - R01 CA122976()
  • NIAMS NIH HHS - R01 AR063724(United States)

Linear Integration of ERK Activity Predominates over Persistence Detection in Fra-1 Regulation.

  • Gillies TE
  • Cell Syst
  • 2017 Dec 27

Literature context: cal School (Janes et al., 2010) RRID:CVCL_0598 Human: 5E/Fra1::mVenus/ERKTR-mC


ERK signaling regulates the expression of target genes, but it is unclear how ERK activity dynamics are interpreted. Here, we investigate this question using simultaneous, live, single-cell imaging of two ERK activity reporters and expression of Fra-1, a target gene controlling epithelial cell identity. We find that Fra-1 is expressed in proportion to the amplitude and duration of ERK activity. In contrast to previous "persistence detector" and "selective filter" models in which Fra-1 expression only occurs when ERK activity persists beyond a threshold duration, our observations demonstrate that the network regulating Fra-1 expression integrates total ERK activity and responds to it linearly. However, exploration of a generalized mathematical model of the Fra-1 coherent feedforward loop demonstrates that it can perform either linear integration or persistence detection, depending on the basal mRNA production rate and protein production delays. Our data indicate that significant basal expression and short delays cause Fra-1 to respond linearly to integrated ERK activity.

Funding information:
  • NCI NIH HHS - CA86862(United States)
  • NCI NIH HHS - P30 CA093373()
  • NIGMS NIH HHS - R01 GM115650()

Force Triggers YAP Nuclear Entry by Regulating Transport across Nuclear Pores.

  • Elosegui-Artola A
  • Cell
  • 2017 Nov 30

Literature context: g et al., 2008N/AMCF10AATCCCat# CRL-10317OligonucleotidessiRNA targeting


YAP is a mechanosensitive transcriptional activator with a critical role in cancer, regeneration, and organ size control. Here, we show that force applied to the nucleus directly drives YAP nuclear translocation by decreasing the mechanical restriction of nuclear pores to molecular transport. Exposure to a stiff environment leads cells to establish a mechanical connection between the nucleus and the cytoskeleton, allowing forces exerted through focal adhesions to reach the nucleus. Force transmission then leads to nuclear flattening, which stretches nuclear pores, reduces their mechanical resistance to molecular transport, and increases YAP nuclear import. The restriction to transport is further regulated by the mechanical stability of the transported protein, which determines both active nuclear transport of YAP and passive transport of small proteins. Our results unveil a mechanosensing mechanism mediated directly by nuclear pores, demonstrated for YAP but with potential general applicability in transcriptional regulation.

Funding information:
  • NIAID NIH HHS - AI 064481(United States)

Mitotic Spindle Assembly and Genomic Stability in Breast Cancer Require PI3K-C2α Scaffolding Function.

  • Gulluni F
  • Cancer Cell
  • 2017 Oct 9

Literature context: RID:CVCL_0598 MCF7 ATCC Cat. # HTB-22; RRID:C


Proper organization of the mitotic spindle is key to genetic stability, but molecular components of inter-microtubule bridges that crosslink kinetochore fibers (K-fibers) are still largely unknown. Here we identify a kinase-independent function of class II phosphoinositide 3-OH kinase α (PI3K-C2α) acting as limiting scaffold protein organizing clathrin and TACC3 complex crosslinking K-fibers. Downregulation of PI3K-C2α causes spindle alterations, delayed anaphase onset, and aneuploidy, indicating that PI3K-C2α expression is required for genomic stability. Reduced abundance of PI3K-C2α in breast cancer models initially impairs tumor growth but later leads to the convergent evolution of fast-growing clones with mitotic checkpoint defects. As a consequence of altered spindle, loss of PI3K-C2α increases sensitivity to taxane-based therapy in pre-clinical models and in neoadjuvant settings.

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: MCF10A ATCC Cat#CRL-10317; RRID:CVCL_0598 hTERT-SD31 Ciccia et al., 2009


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 Class of Environmental and Endogenous Toxins Induces BRCA2 Haploinsufficiency and Genome Instability.

  • Tan SLW
  • Cell
  • 2017 Jun 1

Literature context: 2011N/AHuman: U2OSATCCCat#HTB-96Human: MCF-10AATCCCat#CRL-10317Human: MCF7ATCCCat#HTB-22Human:


Mutations truncating a single copy of the tumor suppressor, BRCA2, cause cancer susceptibility. In cells bearing such heterozygous mutations, we find that a cellular metabolite and ubiquitous environmental toxin, formaldehyde, stalls and destabilizes DNA replication forks, engendering structural chromosomal aberrations. Formaldehyde selectively depletes BRCA2 via proteasomal degradation, a mechanism of toxicity that affects very few additional cellular proteins. Heterozygous BRCA2 truncations, by lowering pre-existing BRCA2 expression, sensitize to BRCA2 haploinsufficiency induced by transient exposure to natural concentrations of formaldehyde. Acetaldehyde, an alcohol catabolite detoxified by ALDH2, precipitates similar effects. Ribonuclease H1 ameliorates replication fork instability and chromosomal aberrations provoked by aldehyde-induced BRCA2 haploinsufficiency, suggesting that BRCA2 inactivation triggers spontaneous mutagenesis during DNA replication via aberrant RNA-DNA hybrids (R-loops). These findings suggest a model wherein carcinogenesis in BRCA2 mutation carriers can be incited by compounds found pervasively in the environment and generated endogenously in certain tissues with implications for public health.

Synergistic interactions with PI3K inhibition that induce apoptosis.

  • Zwang Y
  • Elife
  • 2017 May 31

Literature context: . MCF10A (RRID:CVCL_0598) cells wer


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()

Multiparametric Analysis of Cell Shape Demonstrates that β-PIX Directly Couples YAP Activation to Extracellular Matrix Adhesion.

  • Sero JE
  • Cell Syst
  • 2017 Jan 25

Literature context: 0A human mammary gland cellsATCCCRL-10317MDA-MB-231 human breast tumor ce


Mechanical signals from the extracellular matrix (ECM) and cellular geometry regulate the nuclear translocation of transcriptional regulators such as Yes-associated protein (YAP). Elucidating how physical signals control the activity of mechanosensitive proteins poses a technical challenge, because perturbations that affect cell shape may also affect protein localization indirectly. Here, we present an approach that mitigates confounding effects of cell-shape changes, allowing us to identify direct regulators of YAP localization. This method uses single-cell image analysis and statistical models that exploit the naturally occurring heterogeneity of cellular populations. Through systematic depletion of all human kinases, Rho family GTPases, GEFs, and GTPase activating proteins (GAPs), together with targeted chemical perturbations, we found that β-PIX, a Rac1/Ccd42 GEF, and PAK2, a Rac1/Cdc42 effector, drive both YAP activation and cell-ECM adhesion turnover during cell spreading. Our observations suggest that coupling YAP to adhesion dynamics acts as a mechano-timer, allowing cells to rapidly tune gene expression in response to physical signals.

Funding information:
  • Cancer Research UK - 13478()

Co-transcriptional R-loops are the main cause of estrogen-induced DNA damage.

  • Stork CT
  • Elife
  • 2016 Aug 23

Literature context: RL-10317, RRID:CVCL_0598), where th


The hormone estrogen (E2) binds the estrogen receptor to promote transcription of E2-responsive genes in the breast and other tissues. E2 also has links to genomic instability, and elevated E2 levels are tied to breast cancer. Here, we show that E2 stimulation causes a rapid, global increase in the formation of R-loops, co-transcriptional RNA-DNA products, which in some instances have been linked to DNA damage. We show that E2-dependent R-loop formation and breast cancer rearrangements are highly enriched at E2-responsive genomic loci and that E2 induces DNA replication-dependent double-strand breaks (DSBs). Strikingly, many DSBs that accumulate in response to E2 are R-loop dependent. Thus, R-loops resulting from the E2 transcriptional response are a significant source of DNA damage. This work reveals a novel mechanism by which E2 stimulation leads to genomic instability and highlights how transcriptional programs play an important role in shaping the genomic landscape of DNA damage susceptibility.

Constitutive Cdk2 activity promotes aneuploidy while altering the spindle assembly and tetraploidy checkpoints.

  • Jahn SC
  • J. Cell. Sci.
  • 2013 Mar 1

Literature context: ctivationImmunoblot analysis of MCF10A cell lines treated with cytocha


The cell has many mechanisms for protecting the integrity of its genome. These mechanisms are often weakened or absent in many cancers, leading to high rates of chromosomal instability in tumors. Control of the cell cycle is crucial for the function of these checkpoints, and is frequently lost in cancers as well. Overexpression of Cyclin D1 in a large number of breast cancers causes overactivation of the cyclin-dependent kinases, including Cdk2. Constitutive Cdk2 activation through Cyclin D1 generates tumors in mice that are aneuploid and have many characteristics indicative of chromosomal instability. Expression of these complexes in the MCF10A cell line leads to retinoblastoma protein (Rb) hyperphosphorylation, a subsequent increase in proliferation rate, and increased expression of the spindle assembly checkpoint protein Mad2. This results in a strengthening of the spindle assembly checkpoint and renders cells more sensitive to the spindle poison paclitaxel. Constitutive Rb phosphorylation also causes a weakening of the p53-dependent tetraploidy checkpoint. Cells with overactive Cdk2 fail to arrest after mitotic slippage in the presence of paclitaxel or cytokinesis failure during treatment with cytochalasin-B, generating 8N populations. This additional increase in DNA content appears to further intensify the tetraploidy checkpoint in a step-wise manner. These polyploid cells are not viable long-term, either failing to undergo division or creating daughter cells that are unable to undergo subsequent division. This study raises intriguing questions about the treatment of tumors with overactive Cdk2.

Funding information:
  • NINDS NIH HHS - NS054724(United States)