Featured
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| Open AccessTranscriptional repression of estrogen receptor alpha by YAP reveals the Hippo pathway as therapeutic target for ER+ breast cancer
Hippo signalling is reported to be required for proper ESR1 expression. Here the authors reveal that the transcriptional repression of ESR1 is via LATS-YAP-TEAD-VGLL3 axis and the epigenetic regulation of ESR1 super enhancer in ER + breast cancer.
- Shenghong Ma
- , Tracy Tang
- & Kun-Liang Guan
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Article
| Open AccessProteomic analysis of archival breast cancer clinical specimens identifies biological subtypes with distinct survival outcomes
Protein level information enables the identification of potential biomarkers and therapeutic targets for breast cancer. Here, the authors perform proteomic analysis of 2 cohorts of breast cancer surgical specimens and identify distinct subtypes, immune features and survival outcomes.
- Karama Asleh
- , Gian Luca Negri
- & Gregg B. Morin
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| Open AccessLin28B-high breast cancer cells promote immune suppression in the lung pre-metastatic niche via exosomes and support cancer progression
The establishment of a pre-metastatic niche is a key step preceding metastasis formation. Here the authors show that tumor-intrinsic Lin28B, a RNA-binding protein, has an essential role in the formation of an immune-suppressive pre-metastatic niche, promoting lung metastasis of breast cancer.
- Meiyan Qi
- , Yun Xia
- & Lixing Zhan
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Article
| Open AccessCopy number amplification of ENSA promotes the progression of triple-negative breast cancer via cholesterol biosynthesis
Copy number alterations are pivotal genetic events in triple-negative breast cancer. Here the authors show the amplification of ENSA at the 1q21.3 region promotes the progression of TNBC via up-regulation of cholesterol biosynthesis.
- Yi-Yu Chen
- , Jing-Yu Ge
- & Ke-Da Yu
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Article
| Open AccessPrimary tumor associated macrophages activate programs of invasion and dormancy in disseminating tumor cells
The understanding of the mechanisms underlying the ability of disseminated tumor cells (DTCs) to form metastasis is incomplete. Here, by using high-resolution intravital imaging of the murine lung to track the fate of breast-derived DTCs, the authors show that macrophages within the primary tumor induce a pro-dissemination and pro-dormancy phenotype in tumor cells, favouring their extravasation in the lung.
- Lucia Borriello
- , Anouchka Coste
- & David Entenberg
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Article
| Open AccessThe WID-BC-index identifies women with primary poor prognostic breast cancer based on DNA methylation in cervical samples
Breast cancer is most commonly diagnosed via a needle biopsy. In this study, the authors show that cervical samples from women with breast cancer have a methylation signature different to that of healthy controls.
- James E. Barrett
- , Chiara Herzog
- & Martin Widschwendter
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Article
| Open AccessTranscriptional changes in the mammary gland during lactation revealed by single cell sequencing of cells from human milk
Human mammary tissue remodelling that takes place during pregnancy and lactation remains poorly understood. Here the authors characterize cells in human milk, identifying epithelial cells resembling luminal progenitors and immune cells, contributing insights into this process.
- Alecia-Jane Twigger
- , Lisa K. Engelbrecht
- & Walid T. Khaled
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Article
| Open AccessMapping molecular subtype specific alterations in breast cancer brain metastases identifies clinically relevant vulnerabilities
The molecular landscape of breast cancer brain metastases (BCBM) is still understudied, especially for different breast cancer subtypes. Here, the authors characterise subtype-specific BCBMs using genomics and transcriptomics and identify homologous recombination deficiency as a key therapeutic vulnerability.
- Nicola Cosgrove
- , Damir Varešlija
- & Leonie S. Young
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Article
| Open AccessHIF-1 Interacts with TRIM28 and DNA-PK to release paused RNA polymerase II and activate target gene transcription in response to hypoxia
Hypoxia-inducible factor-1 (HIF-1) is a transcription factor that modulates target gene expression in response to changes in oxygen availability. Here the authors show that HIF-1 forms a complex with TRIM28 and DNA-dependent protein kinase (DNA-PK) that phosphorylates TRIM28. This leads to CDK9 recruitment, which stimulates RNA polymerase II (RNAPII) pause release and transcriptional elongation.
- Yongkang Yang
- , Haiquan Lu
- & Gregg L. Semenza
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Article
| Open AccessMAPK4 promotes triple negative breast cancer growth and reduces tumor sensitivity to PI3K blockade
PI3K inhibitors have limited efficacy in triple negative breast cancer (TNBC). Here, the authors show that MAPK4 activates AKT independent of PI3K and thus promotes tumour growth in a subset of TNBC and that MAPK4 inhibition sensitizes to PI3K blockade in these tumours.’
- Wei Wang
- , Dong Han
- & Feng Yang
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Article
| Open AccessGenomic alterations and evolution of cell clusters in metastatic invasive micropapillary carcinoma of the breast
Invasive micropapillary carcinoma (IMPC) is a highly metastatic rare form of breast cancer but its genomic alterations are largely unknown. Here, the authors show that monoclonal metastatic ancestors share copy-number loss of PRDM16 and IGSF9 and gain of ALDH2 in primary samples from IMPC patients.
- Qianqian Shi
- , Kang Shao
- & Li Fu
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Article
| Open AccessCopper depletion modulates mitochondrial oxidative phosphorylation to impair triple negative breast cancer metastasis
Copper depletion has been reported to improve survival in patients with triple negative breast cancer (TNBC) but the underlying mechanisms are not completely understood. Here, the authors show that copper chelation reduces mitochondrial oxidative phosphorylation leading to decreased TNBC metastasis.
- Divya Ramchandani
- , Mirela Berisa
- & Vivek Mittal
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Article
| Open AccessLive tumor imaging shows macrophage induction and TMEM-mediated enrichment of cancer stem cells during metastatic dissemination
Intravital imaging reveals macrophage-driven de novo induction of cancer stem cells in vivo, and their dramatic enrichment on dissemination through TMEM doorways. These findings provide a mechanism for the validated ability of TMEM doorway density to be prognostic for distant recurrence of metastatic tumors in breast cancer patients.
- Ved P. Sharma
- , Binwu Tang
- & Maja H. Oktay
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Article
| Open AccessNuclear pore protein NUP210 depletion suppresses metastasis through heterochromatin-mediated disruption of tumor cell mechanical response
The involvement of nuclear pore proteins in cellular mechanosensing and metastasis is unclear. Here the authors identify that nuclear pore protein NUP210 promotes metastasis through the interaction with mechanotransducer LINC complex protein and chromatin to regulate mechanosensitive genes.
- Ruhul Amin
- , Anjali Shukla
- & Kent W. Hunter
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Article
| Open AccessCompressive stress-mediated p38 activation required for ERα + phenotype in breast cancer
Reliable luminal estrogen receptor (ERα+) breast cancer models are limited. Here, the authors use patient derived breast epithelial and breast cancer explant cultures grown in several extracellular matrix scaffolds and show that ERα expression is regulated by matrix stiffness via stress-mediated p38 activation and H3K27me3-mediated epigenetic regulation.
- Pauliina M. Munne
- , Lahja Martikainen
- & Juha Klefström
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Article
| Open AccessMammary tumour cells remodel the bone marrow vascular microenvironment to support metastasis
The visualisation of the bone metastasis process in a spatial temporal manner is lacking. Here, the authors use three-dimensional quantitative imaging and show that mouse mammary tumour cells preferentially home to endothelial subtype type H vessels within the bone marrow and remodel this vasculature by producing granulocyte-colony stimulating factor.
- Raymond K. H. Yip
- , Joel S. Rimes
- & Jane E. Visvader
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Article
| Open AccessWhole-genome analysis of Nigerian patients with breast cancer reveals ethnic-driven somatic evolution and distinct genomic subtypes
Breast cancer heterogeneity and tumour evolutionary trajectories remain largely unknown among women of African ancestry. Here, the authors perform whole genome and transcriptome sequencing of Nigerian breast cancer patients and identify unique evolutionary phenomena.
- Naser Ansari-Pour
- , Yonglan Zheng
- & Olufunmilayo I. Olopade
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Article
| Open AccessHigh endogenous CCL2 expression promotes the aggressive phenotype of human inflammatory breast cancer
Inflammatory breast cancer (IBC) is an aggressive form of breast cancer with a poor prognosis. Here the authors report the characterization of a human IBC cell line recapitulating the clinical and histopathological features of the human disease, and implicating its high level of CCL2 in macrophage infiltration and tumor progression.
- Anita Rogic
- , Ila Pant
- & Stuart A. Aaronson
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Article
| Open AccessHER2 + breast cancers evade anti-HER2 therapy via a switch in driver pathway
Resistance to HER2 inhibition in HER2- amplified breast cancer is common in the metastatic setting and the underlying molecular mechanisms remain unknown. Here, the authors, perform genomic profiling of 733 HER2-amplified breast cancers and propose genetic activation of MAPK as a resistance mechanism.
- Alison E. Smith
- , Emanuela Ferraro
- & Sarat Chandarlapaty
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Article
| Open AccessRNF19A-mediated ubiquitination of BARD1 prevents BRCA1/BARD1-dependent homologous recombination
BRCA1 dysfunction sensitizes cancer cells to PARP inhibitors (PARPi) but the underlying mechanism is unclear. Here, the authors identify RNF19A as a determinant of PARPi sensitivity, showing that RNF19A ubiquitinates BARD1, negatively regulates the BRCA1-BARD1 complex, and inhibits homologous recombination.
- Qian Zhu
- , Jinzhou Huang
- & Zhenkun Lou
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Article
| Open AccessAbemaciclib is a potent inhibitor of DYRK1A and HIP kinases involved in transcriptional regulation
Abemaciclib is a third generation CDK-directed drug used in the treatment of HR + /HER2 negative advanced or metastatic breast cancer. Here the authors demonstrate that members of the Homeodomain-interacting protein kinases (HIPKs) HIPK3 and DYRK1A are also targeted by Abemaciclib.
- Ines H. Kaltheuner
- , Kanchan Anand
- & Matthias Geyer
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| Open AccessNeoadjuvant T-DM1/pertuzumab and paclitaxel/trastuzumab/pertuzumab for HER2+ breast cancer in the adaptively randomized I-SPY2 trial
HER2-targeted therapy improves patient’s outcome in early breast cancer. Here, the authors present the efficacy and biomarker analysis of two HER2-targeted combinations (ado-trastuzumab emtansine plus pertuzumab and paclitaxel, trastuzumab and pertuzumab) in the context of the neoadjuvant I-SPY2 phase 2 adaptive platform trial for early breast cancer at high risk of recurrence.
- Amy S. Clark
- , Christina Yau
- & Angela M. DeMichele
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Article
| Open AccessPostpartum breast cancer has a distinct molecular profile that predicts poor outcomes
The molecular differences between postpartum (PPBC) and nulliparous (NPBC) young women breast cancer (YWBC) patients remain unknown. Here the authors perform RNA sequencing and multiplex immunohistochemistry on an FFPE breast cancer cohort and suggest that PPBC is a unique entity within YWBC with poor prognosis.
- Sonali Jindal
- , Nathan D. Pennock
- & Pepper Schedin
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Article
| Open AccessMulti-omics analysis identifies therapeutic vulnerabilities in triple-negative breast cancer subtypes
Triple negative breast cancer can be divided into additional subtypes. Here, using omics analyses, the authors show that in the mesenchymal subtype expression of MHC-1 is repressed and that this can be restored by using drugs that target subunits of the epigenetic modifier PRC2.
- Brian D. Lehmann
- , Antonio Colaprico
- & X. Steven Chen
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Article
| Open AccessDaily caloric restriction limits tumor growth more effectively than caloric cycling regardless of dietary composition
Caloric restriction (CR) has been shown as an effective intervention to reduce tumorigenesis, but alternative less stringent dietary interventions have also been considered. Here, the authors show that in a murine model of breast cancer CR has a larger effect on preventing tumorigenesis and metastasis compared to periodic caloric cycling.
- Laura C. D. Pomatto-Watson
- , Monica Bodogai
- & Rafael de Cabo
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Article
| Open AccessSpatial deconvolution of HER2-positive breast cancer delineates tumor-associated cell type interactions
While transcriptomics have enhanced our understanding for cancer, spatial transcriptomics enable the characterisation of cellular interactions. Here, the authors integrate single cell data with spatial information for HER2 + tumours and develop tools for the prediction of interactions between tumour-infiltrating cells.
- Alma Andersson
- , Ludvig Larsson
- & Joakim Lundeberg
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Article
| Open AccessBRCA2 associates with MCM10 to suppress PRIMPOL-mediated repriming and single-stranded gap formation after DNA damage
Tumor suppressor BRCA2 is known to stabilize and restart stalled DNA replication forks. Here the authors show that BRCA2 is recruited to the replication fork through its interaction with MCM10 and inhibits Primase-Polymerase-mediated repriming, lesion bypass and single strand DNA gap formation after DNA damage.
- Zhihua Kang
- , Pan Fu
- & Bing Xia
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Article
| Open AccessArtificial intelligence system reduces false-positive findings in the interpretation of breast ultrasound exams
Ultrasound is an important imaging modality for the detection and characterization of breast cancer, but it has been noted to have high false-positive rates. Here, the authors present an artificial intelligence system that achieves radiologist-level accuracy in identifying breast cancer in ultrasound imaging.
- Yiqiu Shen
- , Farah E. Shamout
- & Krzysztof J. Geras
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Article
| Open AccessMolecular correlates of response to eribulin and pembrolizumab in hormone receptor-positive metastatic breast cancer
A randomized phase 2 clinical trial has recently shown no benefit of the combination eribulin and pembrolizumab over pembrolizumab alone in HR + metastatic breast cancer patients (NCT03051659). Here, the authors are reporting the final OS data and biomarker analyses on a subset of samples to analyze molecular correlates
- Tanya E. Keenan
- , Jennifer L. Guerriero
- & Sara M. Tolaney
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Article
| Open AccessGenetic variations of DNA bindings of FOXA1 and co-factors in breast cancer susceptibility
The identification of transcription factors (TFs) whose binding sites are affected by risk genetic variants remains crucial. Here, the authors develop a statistical framework to analyse ChIP-seq and GWAS data, identify 22 breast cancer risk-associated TFs and a core TF-transcriptional network for FOXA1 and co-factors.
- Wanqing Wen
- , Zhishan Chen
- & Xingyi Guo
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Article
| Open AccessDNA methylation landscapes of 1538 breast cancers reveal a replication-linked clock, epigenomic instability and cis-regulation
Understanding the molecular mechanisms underlying DNA methylation in cancer and its clinical relevance remains crucial. Here, the authors study RRBS-based profiles of 1538 breast tumours and 244 normal breast tissues from the METABRIC cohort and report epigenomic instability and cis-regulatory effects.
- Rajbir Nath Batra
- , Aviezer Lifshitz
- & Carlos Caldas
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| Open AccessMammary-specific expression of Trim24 establishes a mouse model of human metaplastic breast cancer
Human metaplastic breast cancers (MpBC) are a rare, aggressive subclass of triple-negative breast cancers. Here, the authors show over-expression of histone reader TRIM24 is sufficient to generate tumors with a molecular signature of metabolic dysfunction and EMT in a mouse model of human MpBC.
- Vrutant V. Shah
- , Aundrietta D. Duncan
- & Michelle Craig Barton
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Article
| Open AccessSingle allele loss-of-function mutations select and sculpt conditional cooperative networks in breast cancer
Transposon based screens carried out in mice can identify genes critical for tumourigensis. Here, the authors describe transposon screens in mouse models of breast cancer and highlight a large group of tumour suppressors that could underlie selection for common chromosome arm losses in cancer.
- Nathan F. Schachter
- , Jessica R. Adams
- & Sean E. Egan
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Article
| Open AccessLong non-coding RNA NR2F1-AS1 induces breast cancer lung metastatic dormancy by regulating NR2F1 and ΔNp63
Disseminated tumor cells often become dormant before awakening for metastatic growth. Here, the authors report that the lncRNA, NR2F1-AS1, is upregulated in dormant mesenchymal-like breast cancer stem-like cells and promotes dissemination but inhibits proliferation, leading to metastatic dormancy.
- Yingjie Liu
- , Peiyuan Zhang
- & Guohong Hu
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Article
| Open AccessExosomal miR-19a and IBSP cooperate to induce osteolytic bone metastasis of estrogen receptor-positive breast cancer
Bone metastasis is a major complication of breast cancer (BC) and ER+ tumors have a higher incidence of bone metastasis than ER− tumors. Here, the authors report that miR‐19a in exosomes and the bone matrix protein, IBSP, are upregulated and secreted by bone tropic ER+ BC cells, where they cooperatively induce osteoclastogenesis and promote bone colonization.
- Kerui Wu
- , Jiamei Feng
- & Kounosuke Watabe
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Article
| Open AccessCombined intermittent fasting and ERK inhibition enhance the anti-tumor effects of chemotherapy via the GSK3β-SIRT7 axis
The combination of intermittent fasting and chemotherapy can improve the response to treatment. Here, the authors show that SIRT7 activation is required to inactivate Akt during intermittent fasting and that the combination of intermittent fasting and inhibitors that block the Erk pathway can improve efficacy of treatment.
- Xiaolong Tang
- , Guo Li
- & Baohua Liu
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Article
| Open AccessCo-targeting CDK4/6 and AKT with endocrine therapy prevents progression in CDK4/6 inhibitor and endocrine therapy-resistant breast cancer
CDK4/6 inhibitors in combination with endocrine therapy has shown efficacy in ER + breast cancer patients but resistance can occur. Here, the authors demonstrate that co-targeting CDK4/6 and AKT with endocrine therapy prevents acquired resistance and therapy adaptation.
- Carla L. Alves
- , Sidse Ehmsen
- & Henrik J. Ditzel
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Article
| Open AccessSingle-cell evaluation reveals shifts in the tumor-immune niches that shape and maintain aggressive lesions in the breast
The classification of breast lesions as indolent or aggressive to tailor treatment is crucial. Here, the authors use single-cell transcriptomics and multiparametric imaging of a breast cancer mouse model, report distinct tumor-immune features for the two types of lesions, and suggest the role of IL-17 signaling in disease progression.
- Vidya C. Sinha
- , Amanda L. Rinkenbaugh
- & Helen Piwnica-Worms
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Article
| Open AccessSimultaneous CK2/TNIK/DYRK1 inhibition by 108600 suppresses triple negative breast cancer stem cells and chemotherapy-resistant disease
Finding therapeutic strategies for aggressive triple negative breast cancer (TNBC) is an important challenge in clinical practice. Here, the authors identify a multi-kinases inhibitor with antitumor activity and able overcome chemotherapy resistance of TNBC in vivo.
- Katsutoshi Sato
- , Amol A. Padgaonkar
- & E. Premkumar Reddy
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Article
| Open AccessTEM8 marks neovasculogenic tumor-initiating cells in triple-negative breast cancer
Vasculogenic mimicry (VM) contributes to the development of triple-negative breast cancer. In this study, the authors show that TEM8 is expressed in VM-forming breast cancer stem cells and it promotes stemness and VM differentiation capacity through a RhoC/ROCK1/SMAD5 axis
- Jiahui Xu
- , Xiaoli Yang
- & Suling Liu
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Article
| Open AccessThe HIF target MAFF promotes tumor invasion and metastasis through IL11 and STAT3 signaling
Hypoxia plays a critical role in tumor progression including invasion and metastasis. Here, the authors screened several hypoxia inducible genes and identified the oncogenic role of MAFF in breast cancer metastasis and that it activates IL11/STAT3 pathway.
- Eui Jung Moon
- , Stephano S. Mello
- & Amato J. Giaccia
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Article
| Open AccessEngineered macrophages as near-infrared light activated drug vectors for chemo-photodynamic therapy of primary and bone metastatic breast cancer
Bone metastases are associated with poor prognosis in patients with breast cancer and limited therapeutic options. Here the authors exploit near-infrared light responsive macrophages for the tumor-selective delivery of oxaliplatin prodrug for chemo-photodynamic therapy of primary and bone metastatic breast cancer.
- Yanjuan Huang
- , Zilin Guan
- & Chunshun Zhao
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Article
| Open AccessMorphological screening of mesenchymal mammary tumor organoids to identify drugs that reverse epithelial-mesenchymal transition
The epithelial-mesenchymal transition (EMT) has been implicated in stem cell properties and therapeutic resistance in cancer. Here, the authors show organoids derived from mesenchymal breast cancers exhibit a spikey structure which can be reverted and exploited for screening drugs that reverse EMT.
- Na Zhao
- , Reid T. Powell
- & Jeffrey M. Rosen
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Article
| Open AccessCross-ancestry GWAS meta-analysis identifies six breast cancer loci in African and European ancestry women
GWAS have enhanced our understanding for the genetic basis of breast cancer, but the majority of them were performed for European ancestry populations. Here, the authors use a cross-ancestry approach and report seven new variants associated with breast cancer risk among women of African ancestry.
- Babatunde Adedokun
- , Zhaohui Du
- & Dezheng Huo
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Article
| Open AccessHighly metastatic claudin-low mammary cancers can originate from luminal epithelial cells
The cellular origin and oncogenic drivers promoting claudin-low breast cancer are undefined. Here, the authors report that the consistent activation of oncogenic RAS signaling, as well as regulators of EMT, play a crucial role in the cellular plasticity and maintenance of the mesenchymal and stem cell characteristics of claudin-low mammary cancer cells.
- Patrick D. Rädler
- , Barbara L. Wehde
- & Kay-Uwe Wagner
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Article
| Open AccessAntibody-drug conjugates with dual payloads for combating breast tumor heterogeneity and drug resistance
Intratumor heterogeneity in breast cancer can limit the clinical success of antibody-drug conjugates (ADCs). In this study, the authors develop dual payload Her2-ADCs that show potent anti-tumor activity against heterogeneous breast tumors in vivo.
- Chisato M. Yamazaki
- , Aiko Yamaguchi
- & Kyoji Tsuchikama
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Article
| Open AccessImpairment of a distinct cancer-associated fibroblast population limits tumour growth and metastasis
Endo180, a collagen binding receptor, is highly expressed in a subset of cancer-associated fibroblasts. The authors show, using knockout mice and 3D in vitro assays, that Endo180 depletion impairs tumour fibroblast contractility and viability resulting in reduced tumour growth and metastasis.
- Ute Jungwirth
- , Antoinette van Weverwijk
- & Clare M. Isacke
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Article
| Open AccessTumor microenvironmental cytokines bound to cancer exosomes determine uptake by cytokine receptor-expressing cells and biodistribution
Cancer derived exosomes are reported to promote metastatic dissemination. Here the authors show that cytokines in the tumor microenvironment bind to exosomes via glycosaminoglycan side chains of proteoglycans, and these exosomes are preferentially taken up by specific cell lineages and organs to promote metastasis.
- Luize G. Lima
- , Sunyoung Ham
- & Andreas Möller
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Article
| Open AccessSTAT1 potentiates oxidative stress revealing a targetable vulnerability that increases phenformin efficacy in breast cancer
Complex I inhibition induces oxidative stress leading to cancer cell cytotoxicity. Here, the authors show, in breast cancer models, that inflammatory mediators can potentiate complex I inhibitor phenformin cytotoxicity through STAT1-mediated downregulation of the reactive oxygen species scavenger NQO1.
- Stephanie P. Totten
- , Young Kyuen Im
- & Josie Ursini-Siegel