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| Open AccessUCHL1 provides diagnostic and antimetastatic strategies due to its deubiquitinating effect on HIF-1α
When stabilized, HIF-1 can activate adaptation to hypoxia and metastasis. Here the authors show that upregulation of Ubiquitin C-terminal hydrolase-L1 in human cancers promotes metastasis and correlates with poor prognosis because of its role in opposing ubiquitin-mediated degradation of HIF-1.
- Yoko Goto
- , Lihua Zeng
- & Hiroshi Harada
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Massive parallel sequencing uncovers actionable FGFR2–PPHLN1 fusion and ARAF mutations in intrahepatic cholangiocarcinoma
Intrahepatic cholangiocarcinoma is an aggressive cancer of the bile duct with few treatment options and a below 10% five-year survival rate. Here Sia et al. show a novel FGFR2–PPHLN1 fusion and ARAFmutations that may represent future potential therapeutic targets.
- Daniela Sia
- , Bojan Losic
- & Josep M. Llovet
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Numerical chromosomal instability mediates susceptibility to radiation treatment
Ionizing radiations (IRs) cause widespread genomic damage and can, through unknown mechanisms, lead to changes in chromosome numbers by perturbing the cells undergoing mitosis. Here, the authors investigate the potential mechanism behind the increased susceptibility of mitotic cells to IRs.
- Samuel F. Bakhoum
- , Lilian Kabeche
- & Duane A. Compton
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Clustering of CARMA1 through SH3–GUK domain interactions is required for its activation of NF-κB signalling
Activating mutations in the NF-κB regulator CARMA1 are associated with a form of B-cell lymphoma. Hara et al. show that both physiological and oncogenic CARMA1 signalling can be inhibited by preventing its activation-induced clustering, which is mediated by its SH3 and GUK domains.
- Hiromitsu Hara
- , Tadashi Yokosuka
- & Takashi Saito
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Activating mutations of STAT5B and STAT3 in lymphomas derived from γδ-T or NK cells
NK-cell and γδ-T cell lymphoma share clinic-pathological features; however the driving mutations are largely unknown. Here the authors, using a combination of RNA-Seq analysis, targeted re-sequencing and functional analysis, identify frequent activating mutations in STAT3 and STAT5Bthat may be driver mutations in these diseases.
- Can Küçük
- , Bei Jiang
- & Wing C. Chan
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| Open AccessBCL11A is a triple-negative breast cancer gene with critical functions in stem and progenitor cells
Triple-negative breast cancers (TNBCs) tend to have poor prognosis; however, the mechanisms underlying TNBC pathology are not well understood. Here the authors utilize epidemiologic data and animal models to demonstrate an important role for BCL11A in the genesis and propagation of TNBCs.
- Walid T. Khaled
- , Song Choon Lee
- & Pentao Liu
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| Open AccessGlucocorticoids mediate induction of microRNA-708 to suppress ovarian cancer metastasis through targeting Rap1B
Glucocorticoids show promise for the treatment of ovarian cancer. Here the authors show that glucocorticoids transcriptionally induce the tumour suppressor miR-708, which is downregulated in ovarian cancer, especially in late stages and metastatic tumours.
- Kai-Ti Lin
- , Yu-Ming Yeh
- & Lu-Hai Wang
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Image-guided radiotherapy platform using single nodule conditional lung cancer mouse models
Current genetic mouse models of lung cancer develop multifocal tumours in all lobes, which limits their applicability to model radiotherapy of human disease. Here Herter-Sprie et aldevelop a method to induce single lung tumours in these models, allowing precise evaluation of radiation regiment efficacy.
- Grit S. Herter-Sprie
- , Houari Korideck
- & Kwok-Kin Wong
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| Open AccessTargeting β-catenin signaling for therapeutic intervention in MEN1-deficient pancreatic neuroendocrine tumours
MEN1 gene encodes menin, a nuclear scaffold protein that regulates transcription and is often inactivated in pancreatic neuroendocrine tumours (PNETs). Here Jiang et al. show that MEN1-driven PNET development involves activation of β-catenin, and that β-catenin deletion ameliorates the disease.
- Xiuli Jiang
- , Yanan Cao
- & Guang Ning
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Low MITF/AXL ratio predicts early resistance to multiple targeted drugs in melanoma
Increased expression of MITF transcription factor is thought to promote melanoma progression and kinase inhibitor resistance. Here Muller et al. show that MITF loss is also common in melanomas and confers kinase inhibitor resistance due to upregulation of AXL and other receptor tyrosine kinases.
- Judith Müller
- , Oscar Krijgsman
- & Daniel S. Peeper
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| Open AccessCritical role of lysine 134 methylation on histone H2AX for γ-H2AX production and DNA repair
γ-H2AX The Ser139 phosphorylated form of H2AX, γ-H2AX, is generated in response to DNA double-strand breaks and is involved in the repair process. Here, Sone et al.show that H2AX K134 methylation by SUV39H2 is crucial for the production of γ-H2AX, and that loss of methylation correlates with radio- and chemosensitivity.
- Kenbun Sone
- , Lianhua Piao
- & Ryuji Hamamoto
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Resolving cancer–stroma interfacial signalling and interventions with micropatterned tumour–stromal assays
Gene expression changes at the tumour–stroma interface are associated with epithelial cancer progression. Here, the authors describe a new in vitrosystem based on cell micropatterning and laser microdissection for examining the tumour–stromal interaction.
- Keyue Shen
- , Samantha Luk
- & Biju Parekkadan
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| Open AccessSteroidal and non-steroidal third-generation aromatase inhibitors induce pain-like symptoms via TRPA1
Use of aromatase inhibitors for breast cancer therapy is associated with severe pain symptoms, the underlying mechanism of which is unknown. Here the authors show that in mice, TRPA1 is a major mediator of the proinflammatory and proalgesic actions of aromatase inhibitors.
- Camilla Fusi
- , Serena Materazzi
- & Romina Nassini
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miR-205 acts as a tumour radiosensitizer by targeting ZEB1 and Ubc13
Cancer cells often develop resistance to radiotherapy but the molecular mechanisms responsible remain unclear. Here the authors show that miR-205 promotes radiosensitivity and is downregulated in radioresistant subpopulations of breast cancer cells, and that its loss is associated with poor distant relapse-free survival in breast cancer patients.
- Peijing Zhang
- , Li Wang
- & Li Ma
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Increased MAPK reactivation in early resistance to dabrafenib/trametinib combination therapy of BRAF-mutant metastatic melanoma
Despite the treatment efficacy of combining BRAF and MEK inhibitors, a third of BRAF-mutant metastatic melanoma patients treated with this therapy progress within 6 months. Here, the authors sequence tumours from patients with BRAFV600-mutant melanoma metastases and identify mutations that confer resistance to combination therapy.
- Georgina V. Long
- , Carina Fung
- & Helen Rizos
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| Open AccessERG induces taxane resistance in castration-resistant prostate cancer
Metastatic castration-resistant prostate cancer is treated with the microtubule-stabilizing drugs taxanes, but resistance ultimately develops. Here Galletti et al.show that ERG, a transcription factor commonly overexpressed in prostate cancers, confers taxane resistance by binding to soluble tubulin.
- Giuseppe Galletti
- , Alexandre Matov
- & David S. Rickman
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Targeting TopBP1 at a convergent point of multiple oncogenic pathways for cancer therapy
Topoisomerase IIß-binding protein 1 (TopBP1) is known to suppress apoptosis in cancer and to mediate effects of p53 mutations. Here the authors identify calcein as a lead compound to inhibit TopBP1 and show that calcein has anti-tumour activity in mouse cancer models.
- Pinki Chowdhury
- , Gregory E. Lin
- & Weei-Chin Lin
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Suppression of the FOXM1 transcriptional programme via novel small molecule inhibition
Overexpression of the FOXM1 transcription factor occurs in several cancer and correlates with poor prognoses. Here, the authors identify a novel small molecule capable of displacing FOXM1 from its DNA consensus motif in vitro, displace it from target promoters and downregulate the expression of its target genes cancer cells.
- Michael V. Gormally
- , Thomas S. Dexheimer
- & Shankar Balasubramanian
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Lysophospholipids secreted by splenic macrophages induce chemotherapy resistance via interference with the DNA damage response
It is known that mesenchymal stem cells contribute to chemotherapy resistance by secreting polyunsaturated fatty acids. Here the authors show that macrophages in the spleen secrete lysophosphatidylcholines and contribute to chemotherapy resistance by altering the tumour's DNA damage response.
- Julia M. Houthuijzen
- , Laura G. M. Daenen
- & Emile E Voest
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Vascular channels formed by subpopulations of PECAM1+ melanoma cells
Tumours acquire new vasculature through angiogenesis or through alternative pathways including the less understood vasculogenesis mimicry. Here the authors identify a vasculogenic mimicry-competent subpopulation of melanoma cells that expresses the vascular cell adhesion molecule PECAM1, but not VEGFR-2.
- James M. Dunleavey
- , Lin Xiao
- & Andrew C. Dudley
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LIF negatively regulates tumour-suppressor p53 through Stat3/ID1/MDM2 in colorectal cancers
Leukaemia inhibitory factor (LIF) is a p53 target but its role in cancer is unclear. Here Hu et al.show that LIF confers chemoresistance in colorectal cancer cells by Stat3-mediated upregulation of inhibitor of DNA-binding 1, leading to MDM2 E3 ubiquitin ligase upregulation and p53 degradation.
- Haiyang Yu
- , Xuetian Yue
- & Wenwei Hu
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An endocytosis pathway initiated through neuropilin-1 and regulated by nutrient availability
CendR peptides, based on a C-terminal motif found in neuropilins, have been used to promote drug delivery to tumours by endocytosis. Pang et al. show that CendR peptides are taken up by a mechanistically distinct form of endocytosis that resembles macropinocytosis, and is stimulated by nutrient depletion.
- Hong-Bo Pang
- , Gary B. Braun
- & Erkki Ruoslahti
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| Open AccessDiurnal suppression of EGFR signalling by glucocorticoids and implications for tumour progression and treatment
Glucocorticoids are released in a diurnal pattern. Here, the authors show that EGF receptor (EGFR) signalling is negatively regulated by glucocorticoids, and that EGFR inhibitor has stronger antitumour effects when administered during the resting phase, when glucocorticoids are low, offering potential optimization of cancer therapy regimens.
- Mattia Lauriola
- , Yehoshua Enuka
- & Yosef Yarden
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The pyrido[b]indole MDM2 inhibitor SP-141 exerts potent therapeutic effects in breast cancer models
The oncogene MDM2 has been associated with breast cancer progression and metastasis. Here the authors report the identification of a small molecule that binds MDM2 and that induces its degradation, and that is effective in the treatment of a mouse model of breast cancer.
- Wei Wang
- , Jiang-Jiang Qin
- & Ruiwen Zhang
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Small-molecule Bax agonists for cancer therapy
A major proapoptotic mediator, Bax, is expressed in lung cancer and its activity can be regulated by phosphorylation. Here, the authors screen a library of compounds for their ability to alter the phosphorylation status of Bax and identify therapeutic candidates.
- Meiguo Xin
- , Rui Li
- & Xingming Deng
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| Open AccessMyc inhibition is effective against glioma and reveals a role for Myc in proficient mitosis
Myc has been implicated in the development of multiple types of cancer. Here, the authors explore the therapeutic potential and mechanism of action of Myc inhibition in mouse and human models of glioblastoma, an aggressive type of tumour that is often resistant to conventional therapy.
- Daniela Annibali
- , Jonathan R. Whitfield
- & Laura Soucek
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YAP inhibits squamous transdifferentiation of Lkb1-deficient lung adenocarcinoma through ZEB2-dependent DNp63 repression
Lung adenocarcinomas can convert to squamous cell carcinomas, which is associated with cancer progression and therapy resistance. Here, Gao et al. identify YAP as an essential barrier for this phenotypic conversion through ZEB2-mediated DNP63 repression.
- Yijun Gao
- , Wenjing Zhang
- & Hongbin Ji
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| Open AccessA graphene quantum dot photodynamic therapy agent with high singlet oxygen generation
Photosensitisers are used in cancer therapy to promote the formation of reactive oxygen species on irradiation with light. Here, the authors present a graphene quantum dot photosensitiser with a singlet oxygen quantum yield of approximately 1.3, and investigate its in vitro and in vivoapplications
- Jiechao Ge
- , Minhuan Lan
- & Xiaodong Han
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TRIP13 promotes error-prone nonhomologous end joining and induces chemoresistance in head and neck cancer
Squamous cell carcinoma of the head and neck often becomes resistant to treatment. In this study, Banerjee et al. show that the ATPase TRIP13 can mediate resistance in cells from these tumours by inducing error prone non-homologous end joining DNA repair.
- Rajat Banerjee
- , Nickole Russo
- & Nisha J. D’Silva
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Structural basis for Smoothened receptor modulation and chemoresistance to anticancer drugs
Antagonists of Smoothened, a class F GPCR involved in the hedgehog pathway, have been developed to treat some cancers. Here Wang et al.report structures of Smoothened in complex with antagonists and an agonist, and describe how mutations may result in resistance to anti-Smoothened treatment.
- Chong Wang
- , Huixian Wu
- & Raymond C. Stevens
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Legumain protease-activated TAT-liposome cargo for targeting tumours and their microenvironment
Legumain is a protease found expressed in tumour cells and may be useful in the specific targeting of chemotherapeutics to tumour cells. Here, the authors design nanoparticles that are loaded with doxorubicin and contain a legumain cleavage site; once the nanoparticles enter tumour cells legumain activity results in the release of doxorubicin.
- Ze Liu
- , Min Xiong
- & Rong Xiang
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| Open Access2q36.3 is associated with prognosis for oestrogen receptor-negative breast cancer patients treated with chemotherapy
Studies have shown that breast cancer prognosis is hereditary. Here the authors show that a genetic variant in CCL20, a chemokine ligand involved in immune response, is significantly associated with breast cancer survival and may therefore represent an important therapeutic or prognostic target.
- Jingmei Li
- , Linda S. Lindström
- & Kamila Czene
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| Open AccessMixed lineage kinases activate MEK independently of RAF to mediate resistance to RAF inhibitors
B-Raf is mutated in many melanomas but treatment of the disease with small molecules targeting the mutant protein often results in tumour resistance. Here, the authors show that mixed lineage kinases (MLK1-4) can reactivate the B-Raf signalling pathway in the presence of inhibitors, resulting in drug resistance.
- Anna A. Marusiak
- , Zoe C. Edwards
- & John Brognard
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Enriched variations in TEKT4 and breast cancer resistance to paclitaxel
Paclitaxel is effective in the treatment of breast cancer but predicting which patients might respond to this drug is of clinical importance. Here, Jiang et al. show that germline mutations in TEKT4, a protein that associates with microtubules, are associated with resistance to paclitaxel therapy.
- Yi-Zhou Jiang
- , Ke-Da Yu
- & Zhi-Ming Shao
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Protein grafting of p53TAD onto a leucine zipper scaffold generates a potent HDM dual inhibitor
The protein levels of the tumour suppressor p53 can be negatively regulated by HDM2, which is an attractive target for cancer therapy. In this study, Lee et al. graft the transactivation domain of p53 onto a scaffold protein and show that this binds to HDM2 and inhibits cancer cell growth in vitro.
- Jung-Hoon Lee
- , Eunji Kang
- & Jae Il Lee
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| Open AccessHarnessing photochemical internalization with dual degradable nanoparticles for combinatorial photo–chemotherapy
Photochemical internalisation is the process by which a laser source activates light sensitive compounds for cellular uptake. Here, the authors combine this technique with photo–chemo degradable polymers for the controlled uptake of chemotherapeutics into cancer cells showing increased cell death.
- George Pasparakis
- , Theodore Manouras
- & Panagiotis Argitis
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| Open AccessPorphyrin–phospholipid liposomes permeabilized by near-infrared light
The delivery of therapeutics using an external trigger is an attractive route for the improvement of targeted disease treatment. Here, the authors have discovered a porphyrin–phospholipid liposome for light-controlled membrane permeabilization and use the system to deliver an anticancer drug in vivo.
- Kevin A. Carter
- , Shuai Shao
- & Jonathan F. Lovell
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Three-layered polyplex micelle as a multifunctional nanocarrier platform for light-induced systemic gene transfer
Light-controlled mechanisms for the delivery of drug molecules to cells is a promising route for non-invasive disease therapy. Here, the authors develop a photosensitive polymeric micelle for light-induced gene transfection and show its effectiveness in vivovia systemic administration.
- Takahiro Nomoto
- , Shigeto Fukushima
- & Kazunori Kataoka
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Selective inhibition of BET bromodomain epigenetic signalling interferes with the bone-associated tumour vicious cycle
A major problem in the treatment of bone tumours and metastases is the vicious cycle between bone tumours and resorption. Here, the authors show that treatment with the BET bromodomain inhibitor JQ1 inhibits osteoblast and osteoclast differentiation, and bone tumour development.
- François Lamoureux
- , Marc Baud’huin
- & Benjamin Ory
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| Open AccessLigand substitutions between ruthenium–cymene compounds can control protein versus DNA targeting and anticancer activity
Ruthenium-cymene-based compounds are investigated as potential anticancer drugs. Here, Adhireksan et al.study two ruthenium-containing compounds with varying cytotoxicity and show that differences in ligand structure may explain their activity and binding to different subcellular targets.
- Zenita Adhireksan
- , Gabriela E. Davey
- & Curt A. Davey
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ATP-triggered anticancer drug delivery
Nanoparticles can deliver drugs to tumours but improvements in selectively targeting tumour cells are required. Here, Mo et al. develop nanocarriers that take advantage of high ATP levels in tumour cells and show that these nanoparticles encapsulating the chemotherapeutic doxorubicin can inhibit tumour growth in mice.
- Ran Mo
- , Tianyue Jiang
- & Zhen Gu
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| Open AccessInduction of mitochondrial dysfunction as a strategy for targeting tumour cells in metabolically compromised microenvironments
Quiescent sub-populations of cells in tumours are resistant to traditional chemotherapeutics and are responsible for tumour recurrence. Here, Zhang et al. identify a compound that kills quiescent tumour cells in solid tumour tissue by inducing mitochondrial dysfunction.
- Xiaonan Zhang
- , Mårten Fryknäs
- & Stig Linder
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| Open AccessInactivation of the Hippo tumour suppressor pathway by integrin-linked kinase
The Hippo tumour suppressor pathway is inactivated in many cancer types, but how this occurs is unclear. Here, the authors show that integrin-linked kinase (ILK) has a role in inhibiting the Hippo pathway and pharmacological inhibition of ILK reduces the size of tumours in mice.
- Isabel Serrano
- , Paul C. McDonald
- & Shoukat Dedhar
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Selective cancer targeting with prodrugs activated by histone deacetylases and a tumour-associated protease
Selective targeting of cancer cells may improve therapeutic efficacy while reducing adverse effects. Here, Ueki et al.report selective activation of an anticancer drug upon removal of an acetylated lysine group by histone deacetylases and the tumour-associated protease cathepsin L.
- Nobuhide Ueki
- , Siyeon Lee
- & Michael J. Hayman
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| Open AccessAngiotensin inhibition enhances drug delivery and potentiates chemotherapy by decompressing tumour blood vessels
Hyaluronan is a component of the tumour extracellular matrix. Here, Chauhan et al. show that hyaluronan increases blood pressure in collagen-rich tumours by compressing vessel walls, and that reducing the level of hyaluranon with an angiotensin II inhibitor increases blood flow and drug penetrance in tumours.
- Vikash P. Chauhan
- , John D. Martin
- & Rakesh K. Jain
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| Open AccessTargeting BIG3–PHB2 interaction to overcome tamoxifen resistance in breast cancer cells
Oestrogen receptor-α (ERα) signalling has a role in breast cancer drug resistance. Here, the authors report a synthetic peptide that disrupts the interaction between the signalling molecules BIG3 and PHB2, and thereby suppresses tamoxifen resistance.
- Tetsuro Yoshimaru
- , Masato Komatsu
- & Toyomasa Katagiri
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Non-Darwinian dynamics in therapy-induced cancer drug resistance
Many different factors contribute to the acquisition of drug resistance in cancer cells. Using single-cell analyses of leukaemia cells, the authors here provide evidence for an inductive mode of resistance, where cells express MDR1 in response to drug exposure, rather than selection of pre-existing, partially resistant cells.
- Angela Oliveira Pisco
- , Amy Brock
- & Sui Huang
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| Open AccessATG5 is induced by DNA-damaging agents and promotes mitotic catastrophe independent of autophagy
The protein ATG5 is known to be involved in the formation of autophagosomes. Here, Maskey et al. identify a new role of ATG5 in response to drug-induced DNA damage whereby ATG5 translocates to the nucleus, leading to chromosome misalignment and mitotic catastrophe.
- Dipak Maskey
- , Shida Yousefi
- & Hans-Uwe Simon
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| Open AccessRetinoic acid receptor alpha is associated with tamoxifen resistance in breast cancer
Many patients with breast cancer develop resistance to the drug tamoxifen and relapse. Here Johansson et al. identify the nuclear receptor retinoic acid receptor alpha (RARA) as a marker of tamoxifen resistance and show that RARA expression correlates negatively with relapse-free survival of patients.
- Henrik J. Johansson
- , Betzabe C. Sanchez
- & Janne Lehtiö