Featured
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| Open AccessSingle cell atlas identifies lipid-processing and immunomodulatory endothelial cells in healthy and malignant breast
Tumor blood vessels contribute to cancer growth, invasion and metastasis. Here, by using single cell transcriptomics, the authors report an inventory of endothelial cell heterogeneity in patients with breast cancer, including a subtype that expresses genes involved in lipid processing and is regulated by PPAR-γ.
- Vincent Geldhof
- , Laura P. M. H. de Rooij
- & Peter Carmeliet
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Article
| Open AccessTargeted immunotherapy against distinct cancer-associated fibroblasts overcomes treatment resistance in refractory HER2+ breast tumors
A substantial proportion of HER2+ breast cancer patients do not benefit from HER2-targeted therapy. Here, the authors identify a population of cancer-associated fibroblasts involved in the suppression of trastuzumab-induced ADCC that can be pharmacologically targeted to raise treatment effectiveness in unresponsive tumors.
- Elisa I. Rivas
- , Jenniffer Linares
- & Alexandre Calon
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Article
| Open AccessHigh p16 expression and heterozygous RB1 loss are biomarkers for CDK4/6 inhibitor resistance in ER+ breast cancer
CDK4/6 inhibitor resistance is common in breast cancer. Here, the authors show that p16 overexpression may be linked to reduced efficacy of CDK4/6 inhibition, and show that the combination with PI3K inhibitors may increase anti-tumour effects.
- Marta Palafox
- , Laia Monserrat
- & Violeta Serra
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Article
| Open AccessEpithelial-mesenchymal plasticity determines estrogen receptor positive breast cancer dormancy and epithelial reconversion drives recurrence
The study of tumour dormancy is limited by suitable in vivo models. Here the authors show that mammary intraductal breast cancer (BC) xenografts model estrogen receptor α-positive (ER+) BC dormancy and rapid metastatic progression characteristic of triple-negative (TN) BC. The dormant disseminated ER+ BC cells display characteristics of epithelial-mesenchymal plasticity and forced expression of E-cadherin allows them to overcome dormancy.
- Patrick Aouad
- , Yueyun Zhang
- & Cathrin Brisken
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Article
| Open AccessTemporal profiling of the breast tumour microenvironment reveals collagen XII as a driver of metastasis
The distribution and organisation of matrix molecules in the tumour stroma help shape solid tumour progression. Here they perform temporal proteomic profiling of the matrisome during breast cancer progression and show that collagen XII secreted from CAFs provides a pro-invasive microenvironment.
- Michael Papanicolaou
- , Amelia L. Parker
- & Thomas R. Cox
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Article
| Open AccessAccurate determination of CRISPR-mediated gene fitness in transplantable tumours
Gene fitness and essentiality analyses using in vivo cancer models are challenging due to multiple confounders. Here, the authors develop a quantitative approach to study CRISPR-transduced patient-derived xenografts, which they use to analyse in vivo gene fitness in breast cancers and the biological features that influence uncertainty in fitness estimation.
- Peter Eirew
- , Ciara O’Flanagan
- & Samuel Aparicio
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Article
| Open AccessEngineered bioorthogonal POLY-PROTAC nanoparticles for tumour-specific protein degradation and precise cancer therapy
Proteolysis targeting chimeras (PROTACs) have emerged as promising cancer therapy agents but have suffered from systemic toxicity issues. Here, the authors report on the creation of polymeric PROTAC nanoparticles for tumour targeting delivery and demonstrate protein degradation in vivo, in combination with photodynamic therapy.
- Jing Gao
- , Bo Hou
- & Haijun Yu
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Article
| Open AccessKSTAR: An algorithm to predict patient-specific kinase activities from phosphoproteomic data
Kinases are important drug targets, but predicting their activities from phosphoproteomics data remains challenging. While many existing prediction tools rely on phosphosite-specific quantitative data, Crowl et al. develop a kinase activity prediction algorithm that requires no phosphosite quantification.
- Sam Crowl
- , Ben T. Jordan
- & Kristen M. Naegle
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Article
| Open AccessIntratumor graph neural network recovers hidden prognostic value of multi-biomarker spatial heterogeneity
Cancer prognosis using multiregion sampling is costly and not completely reliable due to the required biomarker homogenisation step. Here, the authors develop an intratumor graph neural network for prognosis in multiregion cancer samples based on in situ biomarkers and gene expression that does not need homogenisation.
- Lida Qiu
- , Deyong Kang
- & Haohua Tu
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Article
| Open AccessHypoxia induces HIF1α-dependent epigenetic vulnerability in triple negative breast cancer to confer immune effector dysfunction and resistance to anti-PD-1 immunotherapy
Hypoxia can promote tumor escape from immune surveillance and immunotherapy. Here, the authors show that hypoxia induces T and NK cell dysfunction through HIF1α-mediated epigenetic suppression of effector gene expression, conferring resistance to anti-PD1 blockade in triple negative breast cancer models.
- Shijun Ma
- , Yue Zhao
- & Qiang Yu
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Article
| Open AccessAMEERA-1 phase 1/2 study of amcenestrant, SAR439859, in postmenopausal women with ER-positive/HER2-negative advanced breast cancer
There is a need for potent and non-toxic estrogen receptor (ER) antagonists to overcome the limitations of existing endocrine therapies. Here the authors report the results from Arm 1 of the Phase 1/2 study (AMEERA-1) among postmenopausal women with ER+/HER2− advanced breast cancer, which evaluates the safety, antitumor activity, pharmacokinetics, and pharmacodynamics of amcenestrant administered as monotherapy.
- Aditya Bardia
- , Sarat Chandarlapaty
- & Mario Campone
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Article
| Open AccessA randomized phase 3 trial of Gemcitabine or Nab-paclitaxel combined with cisPlatin as first-line treatment in patients with metastatic triple-negative breast cancer
Platinum agents, such as carboplatin and cisplatin, have been recommended in combination with gemcitabine for the treatment of metastatic triple negative breast cancer (TNBC). Here the authors report the results of a randomized phase 3 trial to compare the efficacy of first-line nab-paclitaxel/cisplatin to gemcitabine/cisplatin in patients with TNBC.
- Biyun Wang
- , Tao Sun
- & Xichun Hu
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Article
| Open AccessClonal barcoding with qPCR detection enables live cell functional analyses for cancer research
DNA barcoding methods for the analysis of clonal heterogeneity in cancer have been limited in terms of throughput and practical requirements. Here, the authors develop SunCatcher, a rapid and sensitive barcoding approach for live single-cell clonal evolution analysis, and use this method to study breast cancer cell populations.
- Qiuchen Guo
- , Milos Spasic
- & Sandra S. McAllister
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Article
| Open AccessCombinatorial immunotherapies overcome MYC-driven immune evasion in triple negative breast cancer
The oncoprotein c-Myc is often overexpressed in triple negative breast cancer and has a role in tumor progression and resistance to therapy. Here the authors show that elevated MYC expression is correlated with low immune infiltration, diminished MHC-I pathway expression and that CpG/aOX40 treatment could overcome resistance to PD-L1 blockade in MYC-high breast tumors.
- Joyce V. Lee
- , Filomena Housley
- & Andrei Goga
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Article
| Open AccessA scalable, open-source implementation of a large-scale mechanistic model for single cell proliferation and death signaling
Mechanistic models of how single cells respond to different perturbations can help integrate disparate big data sets or predict response to varied drug combinations. Here the authors develop a scalable, open-source pipeline for constructing and simulating large-scale, single-cell mechanistic models, an important building block for clinically-predictive mechanistic models and interpretable big data integration.
- Cemal Erdem
- , Arnab Mutsuddy
- & Marc R. Birtwistle
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Article
| Open AccessGene expression signatures of individual ductal carcinoma in situ lesions identify processes and biomarkers associated with progression towards invasive ductal carcinoma
Progression from ductal carcinoma in situ (DCIS) to invasive ductal carcinoma (IDC) remains poorly understood. Here, the authors analyse over 2700 micro-dissected samples using transcriptomics to identify genes that characterise different stages of DCIS to IDC progression, and identify IDC-associated markers within early-stage lesions.
- Clare A. Rebbeck
- , Jian Xian
- & Gregory J. Hannon
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Article
| Open AccessResults of the phase IIa RADICAL trial of the FGFR inhibitor AZD4547 in endocrine resistant breast cancer
FGFR-1 upregulation has been associated with endocrine therapy resistance in breast cancer patients. Here the authors report the results of a phase IIa study to assess the safety and efficacy of AZD454, an inhibitor of FGFR-1, 2 and 3 receptor tyrosine kinases, in combination with anastrozole or letrozole, in estrogen receptor positive breast cancer patients.
- R. C. Coombes
- , P. D. Badman
- & M. J. Seckl
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Article
| Open AccessEstrogen receptor positive breast cancers have patient specific hormone sensitivities and rely on progesterone receptor
The role of progesterone receptor (PR) and its interplay with estrogen receptor (ER) in breast cancer is controversial. Here, the authors demonstrate that PR can have an ER-independent role in breast cancer growth and metastasis and that its effects are dependent on MYC and androgen receptor signatures.
- Valentina Scabia
- , Ayyakkannu Ayyanan
- & Cathrin Brisken
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Article
| Open AccessYAP inhibits ERα and ER+ breast cancer growth by disrupting a TEAD-ERα signaling axis
Recent studies have reported that oncoprotein YAP can function as tumour suppressor in certain contexts. Here the authors show that inhibition of Hippo signalling or YAP activation blocks ERα transcriptional program and ER + breast cancer growth and mechanistically this is through YAP interfering with TEAD-ERα signalling axis.
- Xu Li
- , Shu Zhuo
- & Jin Jiang
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Article
| Open AccessMulticenter phase II trial of Camrelizumab combined with Apatinib and Eribulin in heavily pretreated patients with advanced triple-negative breast cancer
Therapeutic options for patients with triple-negative breast cancer (TNBC) in later-line setting are limited. Here the authors report the results of a phase 2 clinical trial to evaluate efficacy and safety of the combination of camrelizumab (anti-PD1), apatinib (VEGFR2 inhibitor), and eribulin in patients with heavily pre-treated advanced TNBC.
- Jieqiong Liu
- , Ying Wang
- & Erwei Song
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Article
| Open AccessSTING agonism reprograms tumor-associated macrophages and overcomes resistance to PARP inhibition in BRCA1-deficient models of breast cancer
PARP inhibitor (PARPi) therapy has demonstrated only modest efficacy in advanced breast cancer with BRCA mutations. Here the authors show that, by suppressing PARPi-triggered DNA damage and reducing dsDNA production in BRCA1-deficient breast tumor cells, tumor associated macrophages contribute to PARPi resistance, that can be overcome by STING agonism.
- Qiwei Wang
- , Johann S. Bergholz
- & Jean J. Zhao
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Article
| Open AccessNeddylation inhibition induces glutamine uptake and metabolism by targeting CRL3SPOP E3 ligase in cancer cells
Neddylation inhibition has been reported as a therapy for cancer. Here, the authors show that neddylation inhibition increases glutamine metabolism by stabilizing glutamine transporter ASCT2, therefore targeting ASCT2 improves the anti-cancer effect of neddylation inhibitors.
- Qiyin Zhou
- , Wenyu Lin
- & Yi Sun
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Article
| Open AccessCDK12 promotes tumorigenesis but induces vulnerability to therapies inhibiting folate one-carbon metabolism in breast cancer
Finding biomarkers for targeted therapy is a promising approach to treat cancer. Here, the authors show that in breast cancer preclinical models and patients, CDK12 promotes tumourigenesis but induces selective vulnerability to therapies that target folate one-carbon metabolism.
- M. G. Filippone
- , D. Gaglio
- & S. Pece
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Article
| Open AccessEZH2 engages TGFβ signaling to promote breast cancer bone metastasis via integrin β1-FAK activation
Breast cancer cells are known to metastasize to the bone but why the cells should migrate and metastasize to this particular organ is not clearly understood. Here, the authors show that EZH2 activates an integrin B1 and FAK signaling pathway in breast cancer cells, which activates TGFB signaling to drive metastasis in the bone.
- Lin Zhang
- , Jingkun Qu
- & Dihua Yu
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Article
| Open AccessSpatial epitranscriptomics reveals A-to-I editome specific to cancer stem cell microniches
The spatial context of epitranscriptomic features in the tumour microenvironment remains poorly understood. Here, a method for transcriptomic and epitranscriptomic analysis of immunofluorescence-stained tissue, Select-seq, is applied to stem cell-like microniches in triple negative breast cancer.
- Amos C. Lee
- , Yongju Lee
- & Sunghoon Kwon
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Article
| Open AccessPathogenic BRCA1 variants disrupt PLK1-regulation of mitotic spindle orientation
Female carriers of BRCA1 mutations possess high breast cancer risk, which may reflect deficient growth control of mammary progenitor cells. Here, the authors study progenitor-enriched fractions from these carriers and describe a loss of PLK1-mediated mitotic spindle positioning and an inability of the progeny to acquire features of mature luminal cells.
- Zhengcheng He
- , Ryan Ghorayeb
- & Christopher A. Maxwell
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Article
| Open AccessKMT5A-methylated SNIP1 promotes triple-negative breast cancer metastasis by activating YAP signaling
SNIP1 methylation initiates its oncogenic functions. Here, the authors show that SNIP1 is methylated by KMT5A and this leads to downstream signalling that activates the YAP pathway, resulting in tumorigenesis and metastasis.
- Bo Yu
- , Jun Su
- & Jianming Tang
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Article
| Open AccessESR1 mutant breast cancers show elevated basal cytokeratins and immune activation
Mutations of ESR1, the gene encoding the estrogen receptor alpha, are associated with acquired resistance to therapy in luminalbreast cancer. Here the authors show that ESR1 mutant tumors gain basal-like features with increased expression of basal cytokeratines and immune activation.
- Zheqi Li
- , Olivia McGinn
- & Steffi Oesterreich
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| Open AccessCooperative interaction between ERα and the EMT-inducer ZEB1 reprograms breast cancer cells for bone metastasis
The epithelial mesenchymal transition (EMT) is important in the metastatic spread of cancer cells. Here, the authors show that the EMT transcription factor, ZEB1, can modify estrogen receptor α during EMT and facilitate the migration of breast cancer cells to the bone
- Nastaran Mohammadi Ghahhari
- , Magdalena K. Sznurkowska
- & Didier Picard
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| Open AccessData-driven learning how oncogenic gene expression locally alters heterocellular networks
While mechanistic models play increasing roles in immuno-oncology, hand network curation is current practice. Here the authors use a Bayesian data-driven approach to infer how expression of a secreted oncogene alters the cellular landscape within the tumor.
- David J. Klinke II
- , Audry Fernandez
- & Anika C. Pirkey
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Article
| Open AccessModification of BRCA1-associated breast cancer risk by HMMR overexpression
The effect of hyaluronan-mediated motility receptor (HMMR) expression in BRCA1-associated breast cancer risk remains unknown. Here, HMMR overexpression induces the activation of cGAS-STING and non-canonical NF-κB signalling, instigating an immune permissive environment for breast cancer development.
- Francesca Mateo
- , Zhengcheng He
- & Miquel Angel Pujana
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Article
| Open AccessEnsemble of nucleic acid absolute quantitation modules for copy number variation detection and RNA profiling
Highly multiplexed ddPCR for sensitive nucleic acid quantitation remains challenging due to limited fluorescence channels. Here the authors report quantitative amplicon sequencing (QASeq), a PCR-based molecular barcoding NGS approach which is compatible with high multiplexing.
- Lucia Ruojia Wu
- , Peng Dai
- & David Yu Zhang
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Article
| Open AccessA single-cell analysis of breast cancer cell lines to study tumour heterogeneity and drug response
The impact of tumour heterogeneity on drug response in breast cancer is not fully understood. Here, the authors characterise cell lines from all main breast cancer subtypes using single-cell RNA-seq and train a deconvolution algorithm to predict drug responses in heterogeneous tumour cell populations.
- G. Gambardella
- , G. Viscido
- & D. di Bernardo
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Article
| Open AccessGIT1 protects against breast cancer growth through negative regulation of Notch
Notch signalling is reported to be hyperactivated in oestrogen receptor-negative (ER-) breast cancer. Here the authors show that G protein-coupled receptor kinase-interacting protein 1 (GIT1) negatively regulates Notch signalling and tumour growth in ER- breast cancer by blocking Notch ICD nuclear translocation.
- Songbai Zhang
- , Ayako Miyakawa
- & Per Uhlén
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Article
| Open AccessBiomimetic hydrogel supports initiation and growth of patient-derived breast tumor organoids
Patient-derived tumour organoids are important preclinical models but suffer from variability from the use of basement-membrane extract and cell contamination. Here, the authors report on the development of mimetic nanofibrilar hydrogel which supports tumour organoid growth with reduced batch variability and cell contamination.
- Elisabeth Prince
- , Jennifer Cruickshank
- & Eugenia Kumacheva
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Article
| Open AccessS100A9-CXCL12 activation in BRCA1-mutant breast cancer promotes an immunosuppressive microenvironment associated with resistance to immunotherapy
Defects in BRCA1, a gene involved in homologous recombination DNA repair, are common in triple negative breast cancer. Here the authors show that Brca1 deficiency in preclinical breast cancer models is associated with the accumulation of myeloid derived suppressive cells and resistance to immune checkpoint blockade, that could be overcome by targeting S100A9 and CXCL12.
- Jianjie Li
- , Xiaodong Shu
- & Xiaoling Xu
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Article
| Open Accessp16INK4A-deficiency predicts response to combined HER2 and CDK4/6 inhibition in HER2+ breast cancer brain metastases
HER2+ breast cancer often develop brain metastases (BCBMs) that are difficult to treat. Here, the authors show that p16INK4A loss in BCBMs from HER2+ breast tumors results in resistance to the HER2 inhibitor Tucatinib, and that CDK4/6 inhibition can restore sensitivity to this drug.
- Jing Ni
- , Sheheryar Kabraji
- & Jean J. Zhao
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Article
| Open AccessGpr125 is a unifying hallmark of multiple mammary progenitors coupled to tumor latency
Gpr125 has emerged as a specific marker of mammary stem cells and basal progenitors. Here they show that Gpr125 cells congregate at ductal tips during morphogenesis and amass at tumor margins, and that high Gpr125 predicts early tumor onset and poor outcome in basal breast cancer.
- Elena Spina
- , Julia Simundza
- & Pamela Cowin
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Article
| Open AccessCancer stem cell regulated phenotypic plasticity protects metastasized cancer cells from ferroptosis
The contribution of breast cancer stem cells (BCSCs) to metastasis needs further elucidation. Here, the authors show that BCSCs secrete DKK1 to protect metastasizing cancer cells from ferroptosis via upregulation of SLC7A11, and further show that the combination of a ferroptosis inducer with a DKK1 inhibitor reduces metastasis.
- Mingming Wu
- , Xiao Zhang
- & Tao Zhu
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Article
| 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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Article
| 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