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| Open AccessA synthetic metastatic niche reveals antitumor neutrophils drive breast cancer metastatic dormancy in the lungs
3D scaffolds can be used to recapitulate key aspects of the microenvironment of primary tumors and metastatic organs. Here the authors use subcutaneous porous 3D scaffold implants as a tool to study the immune signals in the lungs of metastatic breast cancer, revealing multifaceted roles of neutrophils in regulating lung metastasis.
- Jing Wang
- , Ramon Ocadiz-Ruiz
- & Lonnie D. Shea
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Article
| Open AccessA multiplex blood-based assay targeting DNA methylation in PBMCs enables early detection of breast cancer
DNA methylation pattern of immune cells can be altered during tumour development. Here, the authors identify 4 DNA methylation markers in peripheral blood mononuclear cells which are predictive of breast cancer across multiple cohorts.
- Tiantian Wang
- , Peilong Li
- & Chuanxin Wang
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Article
| Open AccessDose escalation and expansion cohorts in patients with advanced breast cancer in a Phase I study of the CDK7-inhibitor samuraciclib
Pre-clinical studies have demonstrated the anti-tumor activity of selective inhibitors of CDK7, including samuraciclib. Here the authors report the results from dose escalation and two expansion cohorts in patients with breast cancer of a multi-modular Phase I clinical trial of samuraciclib as anti-cancer treatment.
- R. C. Coombes
- , Sacha Howell
- & Matthew G. Krebs
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Article
| Open AccessObesity-associated changes in molecular biology of primary breast cancer
The association between obesity and breast cancer biology remains understudied in humans. Here, using a large retrospective data collection, the authors identify obesity associated changes in the genomic, transcriptomic profile, and the tumor microenvironment of primary untreated breast tumors.
- Ha-Linh Nguyen
- , Tatjana Geukens
- & Christine Desmedt
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| Open AccessDistinct shared and compartment-enriched oncogenic networks drive primary versus metastatic breast cancer
Distinguishing the drivers of metastasis versus those of the primary tumour in breast cancer remains challenging. Here, the authors explore primary-only, metastatic-only, and shared drivers in breast cancer using mammary-specific transposon mutagenesis screens, which leads to potential therapeutic targets to prevent metastasis.
- Zhe Jiang
- , YoungJun Ju
- & Eldad Zacksenhaus
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| Open AccessOxidative phosphorylation is a metabolic vulnerability of endocrine therapy and palbociclib resistant metastatic breast cancers
Patients with estrogen receptor positive breast cancer (ER + BC) treated with palbociclib (CDK4/6 inhibitor) frequently develop resistance. Here, the authors identify a reliance of palbociclib resistance on oxidative phosphorylation (OXPHOS) and therapeutically target this vulnerability using an OXPHOS inhibitor, restoring sensitivity in ER + BC preclinical models.
- Rania El-Botty
- , Ludivine Morriset
- & Elisabetta Marangoni
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Article
| Open AccessARIH1 activates STING-mediated T-cell activation and sensitizes tumors to immune checkpoint blockade
Loss of the E3 ubiquitin-protein ligase ARIH1 has been associated with cancer escape from anti-tumor immunity. Here the authors show that ARIH1 mediated ubiquitination and degradation of DNA-PKcs trigger activation of STING pathway in tumor cells, sensitizing tumors to immune checkpoint blockade.
- Xiaolan Liu
- , Xufeng Cen
- & Hongguang Xia
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Article
| Open AccessMolecular profiling of aromatase inhibitor sensitive and resistant ER+HER2- postmenopausal breast cancers
Aromatase inhibitors are an effective treatment for ER+ breast cancer, but response is variable. Here, the authors undertake molecular analyse of response from the POETIC trial and identify several factors associated with response.
- Eugene F. Schuster
- , Elena Lopez-Knowles
- & Mitch Dowsett
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Article
| Open AccessCell facilitation promotes growth and survival under drug pressure in breast cancer
In cancer, interactions between treatment-sensitive and resistant cells can influence the effectiveness of therapies. Here, the authors use experimental and mathematical models to explore interactions between ER+ breast cancer cell lineages that are sensitive or resistant to CDK4/6 inhibition, revealing the role of facilitative growth.
- Rena Emond
- , Jason I. Griffiths
- & Andrea H. Bild
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Article
| Open AccessHypoxia induced responses are reflected in the stromal proteome of breast cancer
The role of hypoxia and metabolic reprogramming in breast cancer remains to be explored. Here, the authors investigate the landscape of secreted proteins in response to hypoxia in breast cancer cell lines and identify a stromal-based hypoxia profile in breast cancer tissue.
- Silje Kjølle
- , Kenneth Finne
- & Lars A. Akslen
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Article
| Open AccessA convolutional neural network STIFMap reveals associations between stromal stiffness and EMT in breast cancer
The link between stiffness heterogeneity and tumor cell heterogeneity remains poorly understood. Here, authors propose an AI-informed method that reveals correlations between stromal stiffness and breast cancer cells with a heterogeneous EMT phenotype.
- Connor Stashko
- , Mary-Kate Hayward
- & Valerie M. Weaver
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Article
| Open AccessIdentification of fatty acid amide hydrolase as a metastasis suppressor in breast cancer
Long-term metastatic relapse is observed in patients with luminal breast cancer (BC). Here, the authors show that fatty acid amide hydrolase is a tumour suppressor for lung metastasis in mouse models of BC and a predictor of metastasis in patients with luminal BC.
- Isabel Tundidor
- , Marta Seijo-Vila
- & Eduardo Pérez-Gómez
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Article
| Open Accessp140Cap inhibits β-Catenin in the breast cancer stem cell compartment instructing a protective anti-tumor immune response
The p140Cap adaptor protein is a tumour suppressor associated with improved prognosis in breast cancer. Here, the authors identify a role for p140Cap in preventing the immunosuppressive and pro-tumour function of polymorphonuclear myeloid-derived suppressor cells via downmodulation of the β-Catenin/Tumor Initiating Cells/G-CSF axi
- Vincenzo Salemme
- , Mauro Vedelago
- & Paola Defilippi
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Article
| Open AccessKK-LC-1 as a therapeutic target to eliminate ALDH+ stem cells in triple negative breast cancer
The presence of breast cancer stem cells is associated with therapy resistance in patients with triple-negative breast cancer (TNBC). Here, the authors identify KK-LC-1-mediated YAP signaling as a driver of TNBC stemness and develop a therapeutic molecule to target this axis in preclinical models of TNBC.
- Jiawen Bu
- , Yixiao Zhang
- & Caigang Liu
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Article
| Open AccessDependency of NELF-E-SLUG-KAT2B epigenetic axis in breast cancer carcinogenesis
Transcriptional dysregulation contributes to tumor progression. Here the authors show that transcriptional complex NELF interacts with SLUG, and co-opts KAT2B, to promote the expression of epithelial-mesenchymal transition (EMT) and stemness-associated genes in breast cancer.
- Jieqiong Zhang
- , Zhenhua Hu
- & Wee-Wei Tee
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Article
| Open AccessTMEM25 inhibits monomeric EGFR-mediated STAT3 activation in basal state to suppress triple-negative breast cancer progression
Aberrant EGFR expression is associated with triple-negative breast cancer (TNBC). Here the authors identify that TMEM25 interacts with EGFR and the loss of TMEM25 allows monomeric EGFR-mediated hyperactivation of STAT3 to promote TNBC progression.
- Jing Bi
- , Zhihui Wu
- & Hong-Rui Wang
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Article
| Open AccessLncRNA modulates Hippo-YAP signaling to reprogram iron metabolism
Iron metabolism dysregulation is associated with various diseases including cancer. Here, the authors show that one iron-triggered lncRNA LncRIM regulates cellular iron metabolism effectively by wiring up the Hippo-YAP signaling pathway and promotes breast cancer development.
- Xin-yu He
- , Xiao Fan
- & Aifu Lin
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Article
| Open AccessNucleocytoplasmic transport of active HER2 causes fractional escape from the DCIS-like state
HER2 receptor aberrations are more common in breast DCIS premalignancy than in breast cancer. Here the authors identify a feedback circuit involving HER2 nucleocytoplasmic transport that may explain why some DCIS lesions progress and others do not.
- Lixin Wang
- , B. Bishal Paudel
- & Kevin A. Janes
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Article
| Open AccessAntimicrobial exposure is associated with decreased survival in triple-negative breast cancer
Here, in a cohort of 772 women undergoing triple-negative breast cancer (TNBC) therapy, the authors show that antimicrobial prescription during TNBC treatment associates with inferior overall and breast cancer-specific survival, in turn related to peripheral lymphocyte count and gut microbiome dysbiosis.
- Julia D. Ransohoff
- , Victor Ritter
- & Allison W. Kurian
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| Open AccessDAXX drives de novo lipogenesis and contributes to tumorigenesis
Cancer cells have altered lipid metabolism. Here the authors show that DAXX promotes lipogenesis and tumorigenesis through interaction with SREBP1/2.
- Iqbal Mahmud
- , Guimei Tian
- & Daiqing Liao
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Article
| Open AccessHomologous recombination deficiency derived from whole-genome sequencing predicts platinum response in triple-negative breast cancers
Homologous recombination deficiency is linked with platinum-based chemotherapy response in triple-negative breast cancer (TNBC) but methods to clinically identify these patients are lacking. Here, using patient-derived xenografts of TNBC the authors demonstrate that shallow HRD is predictive of response to platinum-based chemotherapy.
- Petra ter Brugge
- , Sarah C. Moser
- & Elisabetta Marangoni
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Article
| Open AccessVirtual elastography ultrasound via generative adversarial network for breast cancer diagnosis
The current use of elastography ultrasound faces challenges, including vulnerability to subjective manipulation, echo signal attenuation, unknown risks of elastic pressure and high imaging hardware cost. Here, the author shows a virtual elastography to empower low-end ultrasound devices with state-of-art elastography function.
- Zhao Yao
- , Ting Luo
- & JianQiao Zhou
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| Open AccessParallelized multidimensional analytic framework applied to mammary epithelial cells uncovers regulatory principles in EMT
Epithelial-to-mesenchymal transition (EMT) is a complex process regulated at multiple molecular levels. Here, the authors implement an analytic framework - PAMAF - to integrate data from twelve distinct omics modalities, which they use to understand the molecular changes and regulation during EMT in vitro.
- Indranil Paul
- , Dante Bolzan
- & Andrew Emili
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Article
| Open AccessEpigenetic regulation of Neuregulin 1 promotes breast cancer progression associated to hyperglycemia
Despite hyperglycemia has been associated to breast cancer, the underlying mechanisms are not completely understood. Here, the authors show that epigenetic regulation of Nrg1 gene during hyperglycemia promotes breast cancer development.
- Changhu Lee
- , Min Kim
- & Jiyoung Park
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| Open AccessMiXcan: a framework for cell-type-aware transcriptome-wide association studies with an application to breast cancer
Conventional transcriptome-wide association study (TWAS) approaches predict genetically regulated gene expression at the tissue level. Here, the authors develop a framework for cell-type-aware TWAS that predicts cell-type level expression from genotype data and identifies disease-associated genes with cell-type-specific effects.
- Xiaoyu Song
- , Jiayi Ji
- & Weiva Sieh
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Article
| Open AccessNiche stiffness sustains cancer stemness via TAZ and NANOG phase separation
Stromal cells in the tumour microenvironment are reported to regulate cancer stemness via biomechanical signals. Here the authors show that TAZ activated by biomechanical cues enhanced cancer stem cell properties via phase separation with Nanog.
- Xinwei Liu
- , Yingying Ye
- & Qiyi Zhao
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Article
| Open AccessCD26-negative and CD26-positive tissue-resident fibroblasts contribute to functionally distinct CAF subpopulations in breast cancer
The origin of cancer-associated fibroblasts (CAFs) in cancer remains to be identified. Here, single-cell transcriptomics, in vivo and in vitro studies suggest that CD26+ and CD26- normal fibroblasts transform into distinct CAF subpopulations in mouse models of breast cancer.
- Julia M. Houthuijzen
- , Roebi de Bruijn
- & Jos Jonkers
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| Open AccessA comprehensive single-cell map of T cell exhaustion-associated immune environments in human breast cancer
T cell exhaustion in breast tumours remains to be fully characterised. Here, single cell transcriptomics and imaging mass cytometry analysis of luminal breast tumours with or without exhausted T cells suggests distinct patterns of PD-1 and CXCL13 expression in T cells, and of MHC-I, but not PD-L1, expression in tumour cells.
- Sandra Tietscher
- , Johanna Wagner
- & Bernd Bodenmiller
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Article
| Open AccessDesign of a self-driven probiotic-CRISPR/Cas9 nanosystem for sono-immunometabolic cancer therapy
Recently, strategies based on the integration of nanotechnology with microbial carriers have been proposed for cancer therapy. Here the authors report the design of an ultrasound-controlled CRISPR/Cas9 gene editing system for IDO1 silencing compounded with the probiotic Lactobacillus rhamnosus GG, showing the induction of anti-tumor immune responses in preclinical cancer models.
- Jifeng Yu
- , Bangguo Zhou
- & Huixiong Xu
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Article
| Open AccessExosomal miR-1304-3p promotes breast cancer progression in African Americans by activating cancer-associated adipocytes
The molecular mechanisms explaining racial disparity in breast cancer mortality are not completely elucidated. Here, the authors show that an African-associated SNP in American breast cancer patients, leads to higher levels of microRNA miR-1304-3p which promotes cancer by increasing lipids availability.
- Dan Zhao
- , Kerui Wu
- & Kounosuke Watabe
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Article
| Open AccessBreast cancer prevention by short-term inhibition of TGFβ signaling
TGFβ signalling is reported to regulate hormone-responsive mammary epithelial progenitors that are associated with breast cancer risk. Here, the authors find that short-term TGFBR1 inhibition prevents tumour formation in rat breast cancer models and identify a TGFBR1 inhibition-responsive sub-population of mammary epithelial cells, which is associated with human breast cancer risk.
- Maša Alečković
- , Simona Cristea
- & Kornelia Polyak
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| Open AccessPhosphoproteomic analysis of neoadjuvant breast cancer suggests that increased sensitivity to paclitaxel is driven by CDK4 and filamin A
Phosphoproteomics is a promising tool for identifying biomarkers of treatment response in cancer. Here, the authors analyse proteomics profiling of HER2-negative female breast cancer patients and identify potential predictors of paclitaxel response.
- S. Mouron
- , M. J. Bueno
- & M. Quintela-Fandino
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Article
| Open AccessTissue and liquid biopsy profiling reveal convergent tumor evolution and therapy evasion in breast cancer
Liquid biopsies could be valuable tools to monitor breast cancer progression and evolution. Here, the authors investigate genomic profiling of tissue and liquid biopsies in a large cohort of patients with breast cancer during the course of therapy to characterise tumour evolution and acquired mutations.
- Smruthy Sivakumar
- , Dexter X. Jin
- & Ethan S. Sokol
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| Open AccessA framework for clinical cancer subtyping from nucleosome profiling of cell-free DNA
Nucleosome profiling from cell-free DNA (cfDNA) represents a potential approach for cancer detection and classification. Here, the authors develop Griffin, a computational framework for tumour subtype classification based on cfDNA nucleosome profiling that can work with ultra-low pass sequencing data.
- Anna-Lisa Doebley
- , Minjeong Ko
- & Gavin Ha
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Article
| Open AccessEZH2-H3K27me3 mediated KRT14 upregulation promotes TNBC peritoneal metastasis
Enhancer of zeste homolog 2 (EZH2) has been associated with poor prognosis in triple negative breast cancer (TNBC). Here, the authors suggest a potential role for trimethylation function of EZH2 in driving peritoneal metastasis in TNBC.
- Ayushi Verma
- , Akhilesh Singh
- & Dipak Datta
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Article
| Open AccessBreast cancer plasticity is restricted by a LATS1-NCOR1 repressive axis
LATS1 is reported to regulate the transition of luminal-basal-like cell plasticity in breast cancer. Here the authors report that LATS1 limits the progression of luminal breast cancer by associating with NCOR1 nuclear corepressor to repress ERα-downregulated genes in luminal cells.
- Yael Aylon
- , Noa Furth
- & Moshe Oren
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Article
| Open AccessInactivation of LATS1/2 drives luminal-basal plasticity to initiate basal-like mammary carcinomas
LATS1/2 kinases are reported to be tumour suppressors in many cancers. Here the authors show that conditional deletion of LATS1/2 in the mature mouse luminal mammary epithelium leads to luminal-basal plasticity and development of basal-like carcinomas.
- Joseph G. Kern
- , Andrew M. Tilston-Lunel
- & Xaralabos Varelas
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Article
| Open AccessLong noncoding RNA DIO3OS induces glycolytic-dominant metabolic reprogramming to promote aromatase inhibitor resistance in breast cancer
While aromatase inhibitors (AI) are an effective treatment for patients with estrogen receptor positive breast cancer, resistance presents a major obstacle. Here, the authors identify DIO3OS, a long noncoding RNA, as a driver of AI-resistance in breast cancer through the enhancement of aerobic glycolysis.
- Xueman Chen
- , Rong Luo
- & Erwei Song
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Article
| Open AccessA multicentre single arm phase 2 trial of neoadjuvant pyrotinib and letrozole plus dalpiciclib for triple-positive breast cancer
Neoadjuvant therapy is recommended for patients with locally advanced breast cancer. Here the authors report the results of a phase 2 clinical trial of oral neoadjuvant therapy with pyrotinib (pan-HER tyrosine kinase inhibitor), letrozole (aromatase inhibitor) and dalpiciclib (CDK4/6 inhibitor) in patients with treatment-naïve and stage II-III triple positive breast cancer.
- Nan Niu
- , Fang Qiu
- & Caigang Liu
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Article
| Open AccessSingle cell profiling of primary and paired metastatic lymph node tumors in breast cancer patients
Lymph node metastasized tumours (LNMT) in breast cancer have not been comprehensively characterised. Here, the authors perform single cell RNA sequencing analysis of paired primary and LNMT breast cancer samples and suggest a more immunosuppressive tumour microenvironment in the latter.
- Tong Liu
- , Cheng Liu
- & Hongquan Zhang
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Article
| Open AccessCryo-EM reveals the architecture of the PELP1-WDR18 molecular scaffold
PELP1 is a large scaffolding protein implicated in many cellular activities, including ribosome assembly as part of the Rix1 complex, comprising PELP1, WDR18, TEX10 and other components. Here, authors present the cryo-EM structure of PELP1 in complex with its binding partner WDR18, revealing the architecture of PELP1's numerous signaling motifs.
- Jacob Gordon
- , Fleur L. Chapus
- & Robin E. Stanley
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Article
| Open AccessDeep learning-based image analysis predicts PD-L1 status from H&E-stained histopathology images in breast cancer
Programmed death ligand-1 (PD-L1) has been recently adopted for breast cancer as a predictive biomarker for immunotherapies. Here, the authors show that PD-L1 expression can be predicted from H&E-stained images using deep learning.
- Gil Shamai
- , Amir Livne
- & Ron Kimmel
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Article
| Open AccessDNA barcoding reveals ongoing immunoediting of clonal cancer populations during metastatic progression and immunotherapy response
Understanding the molecular mechanisms of cancer immunoediting could provide insight into resistance to immunotherapy. Here, DNA barcoding provides evidence of ongoing immunoediting during metastasis and treatment with anti-PD1 and anti-CTLA4, and identifies cancer cell clones with unique immune evasive phenotypes.
- Louise A. Baldwin
- , Nenad Bartonicek
- & Simon Junankar
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Article
| Open AccessAnalysis of matched primary and recurrent BRCA1/2 mutation-associated tumors identifies recurrence-specific drivers
Carriers of pathogenic BRCA1/2 variants have a higher risk of breast and ovarian cancers, which recur frequently. Here, the authors sequence primary and recurrent tumours of BRCA1/2 mutation carriers, finding PARP1 amplifications, differential BRCA2 isoform usage, and discordant loss of heterozygosity that are associated with recurrence.
- Jennifer B. Shah
- , Dana Pueschl
- & Katherine L. Nathanson
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Article
| Open AccessMYC promotes immune-suppression in triple-negative breast cancer via inhibition of interferon signaling
Tripe-negative breast cancers poorly respond to immune checkpoint inhibition therapy, due to their immune-hostile tumour microenvironment. Authors here show that the oncogene MYC plays a pivotal role in suppressing anti-tumour immunity via directly regulating the transcription of interferon signalling genes.
- Dario Zimmerli
- , Chiara S. Brambillasca
- & Jos Jonkers
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Article
| Open AccessFOXQ1 recruits the MLL complex to activate transcription of EMT and promote breast cancer metastasis
Forkhead box transcription factor, FOXQ1 is reported to promote epithelial-mesenchymal transition (EMT) and cancer metastasis. Here the authors show that FOXQ1 recruits the KMT2/MLL histone methyltransferase complex as a transcriptional coactivator to activate EMT programme in breast cancer.
- Allison V. Mitchell
- , Ling Wu
- & Guojun Wu
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Article
| Open AccessA phase I study of an adenoviral vector delivering a MUC1/CD40-ligand fusion protein in patients with advanced adenocarcinoma
Ad-sig-hMUC1/ecdCD40L is a recombinant adenovirus vaccine comprising human MUC1 antigen fused to the extracellular domain of the CD40 ligand. Here the authors report the result of a phase I clinical trial of Ad-sig-hMUC1/ecdCD40L in patients with advanced adenocarcinoma.
- Tira J. Tan
- , W. X. Gladys Ang
- & Han Chong Toh
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Article
| Open AccessComputational pharmacogenomic screen identifies drugs that potentiate the anti-breast cancer activity of statins
Statins are promising for breast cancer therapy; dipyridamole can potentiate their effects, but is contraindicated in some cases. Here, the authors develop a pharmacogenomics pipeline to predict other compounds that potentiate statins, and validate the top candidates in cell line screens and 3D cultures.
- Jenna E. van Leeuwen
- , Wail Ba-Alawi
- & Deena M. A. Gendoo
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Article
| Open AccessPolarized NHE1 and SWELL1 regulate migration direction, efficiency and metastasis
Cell migration regulates diverse (patho)physiological processes, including cancer metastasis. Here the authors show that the chloride ion channel SWELL1 and the ion exchanger NHE1 are preferentially enriched at the trailing and leading edges, respectively, of migrating cells and regulate cell volume to propel confined cells, favouring breast cancer cell extravasation and metastasis.
- Yuqi Zhang
- , Yizeng Li
- & Konstantinos Konstantopoulos