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| Open AccessHuR controls glutaminase RNA metabolism
Changes in the expression of the RNA-binding protein HuR are common in several cancers. Here, the authors show that HuR regulates glutaminase mRNA metabolism in the context of breast cancer. This work reveals that dual inhibition of HuR and glutaminase may have therapeutic potential.
- Douglas Adamoski
- , Larissa M. dos Reis
- & Sandra Martha Gomes Dias
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Article
| Open AccessO-GlcNAcylation of MITF regulates its activity and CDK4/6 inhibitor resistance in breast cancer
Targeting CDK4/6 in breast cancer has been demonstrated to be initially effective but often, resistance develops. Here, the authors identify microphthalmia-associated transcription factor-A (MITF-A) as a driver of CDK4/6 inhibitor resistance in breast cancer and show that MITF-A activity is mediated through O-GlcNAcylation at Serine 49, promoting its nuclear import.
- Yi Zhang
- , Shuyan Zhou
- & Wenge Zhu
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Article
| Open AccessC-terminally phosphorylated p27 activates self-renewal driver genes to program cancer stem cell expansion, mammary hyperplasia and cancer
Cancer stem cells (CSCs) have important roles in tumour initiation, metastasis and treatment resistance. Here, the authors show that C-terminally phosphorylated p27, together with STAT3, mediates the transcriptional regulation of CSC expansion, increasing cancer formation and metastasis in preclinical breast cancer models.
- Seyedeh Fatemeh Razavipour
- , Hyunho Yoon
- & Joyce M. Slingerland
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Article
| Open AccessProgressive senescence programs induce intrinsic vulnerability to aging-related female breast cancer
Aging-related cancer incidence remains not fully understood. Here, the authors depict a progressive process of senescence in murine mammary stem cells at single-cell resolution, which is governed by the transcription factor Bcl11b and associated with enhanced chemical-induced tumorigenesis in aged mice.
- Huiru Bai
- , Xiaoqin Liu
- & Shang Cai
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Article
| Open AccessHER2-targeting antibody drug conjugate FS-1502 in HER2-expressing metastatic breast cancer: a phase 1a/1b trial
Safety concerns limit the success of HER2-targeting antibody-drug conjugates (ADCs) for the treatment of HER2-postive breast cancer. Here, the authors present a phase 1a/b trial reporting the safety and preliminary efficacy of FS-1502, an anti-HER2 ADC with a cancer-selective cleavable linker, for the treatment of HER2-positive metastatic breast cancer.
- Qiao Li
- , Ying Cheng
- & Binghe Xu
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Article
| Open AccessGlycolysis inhibition induces anti-tumor central memory CD8+T cell differentiation upon combination with microwave ablation therapy
Central memory CD8+ T cells (Tcm) are important for lasting anti-tumour immunity and their differentiation is determined by underpinning transcriptional and metabolic regulation. Authors here show that although microwave ablation (MWA) cancer therapy induces T cells to acquire some of the gene expression features of Tcms, but the full metabolic remodeling required for functionality is only achieved if glycolysis is inhibited simultaneously.
- Xinyu Tang
- , Xinrui Mao
- & Wenbin Zhou
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| Open AccessBreast cancer cell-secreted miR-199b-5p hijacks neurometabolic coupling to promote brain metastasis
Breast cancer metastasis to the brain is rising in prevalence and is an increasingly lethal threat to the patients. Here, the authors show miR-199b-5p, secreted by some breast cancer cells and detected at a higher level in patients with brain metastases, impairs the metabolic coupling between neurons and astrocytes to facilitate development of brain metastasis.
- Xianhui Ruan
- , Wei Yan
- & Shizhen Emily Wang
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Article
| Open AccessDysfunctional adipocytes promote tumor progression through YAP/TAZ-dependent cancer-associated adipocyte transformation
The impact of obesity on cancer remains insufficiently explored. Here the authors show that in mouse models, dysfunctional adipocytes exhibit low levels of BECN1 which induce YAP/TAZ activity to promote breast and colorectal tumor progression.
- Yaechan Song
- , Heeju Na
- & Han-Woong Lee
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Article
| Open AccessMammographic density mediates the protective effect of early-life body size on breast cancer risk
Mammographic density is known to be linked to breast cancer risk. Here, the authors use Mendelian randomization to estimate the effects of childhood body size and age at menarche on density phenotypes and breast cancer risk.
- Marina Vabistsevits
- , George Davey Smith
- & Eleanor Sanderson
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Article
| Open AccessLongitudinal molecular profiling elucidates immunometabolism dynamics in breast cancer
Although metabolic reprogramming within the tumour microenvironment (TME) has been reported in breast cancer, whether and how this evolves during treatment remains unclear. Here, the authors use multiple ‘omic’ analyses to examine this question in patients with breast cancer undergoing neoadjuvant chemotherapy.
- Kang Wang
- , Ioannis Zerdes
- & Theodoros Foukakis
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Article
| Open AccessUsing genome and transcriptome data from African-ancestry female participants to identify putative breast cancer susceptibility genes
Here, the authors integrate genomic and transcriptomic data obtained from African-ancestry female participants and identify six genes associated with breast cancer risk which provides biological insights into this common cancer in an underrepresented population.
- Jie Ping
- , Guochong Jia
- & Wei Zheng
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Article
| Open AccessLoss of NEDD8 in cancer cells causes vulnerability to immune checkpoint blockade in triple-negative breast cancer
NEDD8 is a ubiquitin-like protein that governs protein neddylation, previously demonstrated to be essential for cell survival. Here the authors show that NEDD8 loss in breast cancer cells is associated with enhanced immunogenicity and increased sensitivity to PD-1 blockade in preclinical cancer models.
- Irineos Papakyriacou
- , Ginte Kutkaite
- & Yumeng Mao
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Article
| Open AccessWild-type IDH2 is a therapeutic target for triple-negative breast cancer
Isocitrate dehydrogenase (IDH) mutations are associated with cancer development and IDH-mutant inhibitors are approved to treat IDH-mutant cancer. Here, the authors show in preclinical murine models that wild-type IDH2 is a potential therapeutic target for triple-negative breast cancer.
- Jiang-jiang Li
- , Tiantian Yu
- & Peng Huang
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Article
| Open AccessConcomitant medication, comorbidity and survival in patients with breast cancer
Preliminary epidemiological evidence suggests that some non-cancer medications may affect breast cancer risk, recurrence, and survival. In this study, the authors utilized a nationwide database of breast cancer patients to estimate the association between frequently used drugs taken prior to diagnosis and breast cancer prognosis. And they identified 16 drugs associated with breast cancer outcomes.
- Elise Dumas
- , Beatriz Grandal Rejo
- & Anne-Sophie Hamy
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| Open AccessDeciphering the spatial landscape and plasticity of immunosuppressive fibroblasts in breast cancer
The heterogeneity of cancer associated fibroblasts (CAFs) in breast cancer has been previously described. Here the authors provide further insights into the spatial landscape and plasticity of immunosuppressive fibroblasts in breast cancer.
- Hugo Croizer
- , Rana Mhaidly
- & Fatima Mechta-Grigoriou
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Article
| Open AccessAdjuvant nivolumab, capecitabine or the combination in patients with residual triple-negative breast cancer: the OXEL randomized phase II study
Post-neoadjuvant treatment options for patients with triple-negative breast cancer (TNBC) include the chemo-drug capecitabine but also immune checkpoint inhibitors. Here the authors report the results of a phase II study of adjuvant nivolumab, capecitabine or the combination in patients with residual TNBC.
- Filipa Lynce
- , Candace Mainor
- & Claudine Isaacs
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Article
| Open AccessExemestane plus everolimus and palbociclib in metastatic breast cancer: clinical response and genomic/transcriptomic determinants of resistance in a phase I/II trial
Intrinsic and acquired resistances to CDK4/6 inhibitors have been described in patients with breast cancer. Here the authors report the results from a phase I/II clinical trial of the aromatase inhibitor exemestane plus everolimus (mTOR inhibitor) and palbociclib (CDK4/6i) in patients with metastatic breast cancer, assessing safety, clinical efficacy, as well as genomic and transcriptomic determinants of resistance.
- Jorge Gómez Tejeda Zañudo
- , Romualdo Barroso-Sousa
- & Nikhil Wagle
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Article
| Open AccessPRMT5 is an actionable therapeutic target in CDK4/6 inhibitor-resistant ER+/RB-deficient breast cancer
CDK4/6 inhibitors have improved outcomes for patients with ER+ breast cancer, however, those with loss of RB1 function often fail to respond. Here, the authors identify a vulnerability of ER + /RB1- breast cancer on PRMT5 and via dual blockade of ER and PRMT5 therapeutically target this in patient-derived xenograft models.
- Chang-Ching Lin
- , Tsung-Cheng Chang
- & Carlos L. Arteaga
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| Open AccessNeoadjuvant–adjuvant pertuzumab in HER2-positive early breast cancer: final analysis of the randomized phase III PEONY trial
Previously, the authors reported the primary analysis of a phase III randomized control trial investigating dual HER2 blockade in HER2-positive early/locally advanced breast cancer. Here, the authors report the long-term efficacy and safety analysis of this trial.
- Liang Huang
- , Da Pang
- & Zhimin Shao
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Article
| Open AccessGRB2 stabilizes RAD51 at reversed replication forks suppressing genomic instability and innate immunity against cancer
GRB2 is known for its role in Receptor Tyrosine Kinase and RAS signaling. Here the authors unveil a GRB2 function and mechanism for DNA replication fork protection. GRB2 alleviates oncogenic replication stress, and in doing so, averts cancer immune destruction by inhibiting cGAS/STING and pro-inflammatory cytokine production.
- Zu Ye
- , Shengfeng Xu
- & Zamal Ahmed
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| Open AccessElevated extracellular matrix protein 1 in circulating extracellular vesicles supports breast cancer progression under obesity conditions
Extracellular vesicles are reported to regulate tumorigenesis. Here, the authors show that under obesity conditions, increased extracellular matrix protein 1 protein levels in circulating small extracellular vesicles induce breast cancer growth and metastasis.
- Keyang Xu
- , Ai Fu
- & Hiu Yee Kwan
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Article
| Open AccessConverging and evolving immuno-genomic routes toward immune escape in breast cancer
Immune response during breast cancer progression remains to be explored. Here, the characterisation of sequential and parallel multiregion samples of an index patient and a cohort of metastatic triple-negative breast cancers reveals convergent immune evasion mechanisms and an increase in tumor genomic heterogeneity.
- Juan Blanco-Heredia
- , Carla Anjos Souza
- & Leticia De Mattos-Arruda
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| Open AccessMeiotic protein SYCP2 confers resistance to DNA-damaging agents through R-loop-mediated DNA repair
Aberrant expression of Synaptonemal complex protein 2 (SYCP2) in breast and ovarian cancers is associated with resistance to drugs targeting the DNA damage response. Here the authors show that SYCP2 confers drug resistance by promoting R-loop formation during transcription-coupled homologous recombination.
- Yumin Wang
- , Boya Gao
- & Li Lan
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Article
| Open AccessStructural optimization of siRNA conjugates for albumin binding achieves effective MCL1-directed cancer therapy
Limited tumor cell delivery is a major challenge for the efficacious delivery of siRNAs to silence traditionally undruggable oncogenes. Here the authors optimize siRNAs for in situ binding to albumin through C18 lipid modifications and show the application of the lead conjugate structure for targeting MCL1 in orthotopic breast tumors in mice.
- Ella N. Hoogenboezem
- , Shrusti S. Patel
- & Craig L. Duvall
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| Open AccessThe anti-PD-L1/CTLA-4 bispecific antibody KN046 in combination with nab-paclitaxel in first-line treatment of metastatic triple-negative breast cancer: a multicenter phase II trial
KN046 is a recombinant anti-PD-L1/CTLA-4 bispecific antibody that has shown clinical activity in different advanced solid tumors. Here the authors report the results of a phase II study of KN046 in combination with nab-paclitaxel as first-line treatment of metastatic triple-negative breast cancer.
- Qiao Li
- , Jiaxuan Liu
- & Binghe Xu
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Article
| Open AccessNeutral ceramidase regulates breast cancer progression by metabolic programming of TREM2-associated macrophages
Ceramide, a central molecule in sphingolipid metabolism, has been shown to affect the development and functionality of myeloid cells. Here the authors report that myeloid deficiency of neutral ceramidase (NcDase), the enzyme converting ceramide into sphingosine, induces an immunosuppressive phenotype of tumor associated macrophages, linked to T cell exhaustion in breast cancer preclinical models.
- Rui Sun
- , Chao Lei
- & Zhongbin Deng
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Article
| Open AccessFLIP(C1orf112)-FIGNL1 complex regulates RAD51 chromatin association to promote viability after replication stress
Recombination is essential for life. Here, the authors characterize FLIP as a novel regulator of the key recombination protein RAD51’s functions. FLIP loss caused marked sensitivity to DNA damage, increased DNA breakage and defective replication.
- Jessica D. Tischler
- , Hiroshi Tsuchida
- & Richard O. Adeyemi
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Article
| Open AccessDesign-rules for stapled peptides with in vivo activity and their application to Mdm2/X antagonists
Stapled α-helical peptides are promising for targeting challenging targets such as transcription factors, but achieving sufficient cell permeability while avoiding off-target cleavage is difficult. Here, the authors present workflows for identifying stapled peptides against Mdm2(X) with in vivo activity and no off-target effects based on comprehensive investigations of their properties.
- Arun Chandramohan
- , Hubert Josien
- & Anthony W. Partridge
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| Open AccessThe HER2-directed antibody-drug conjugate DHES0815A in advanced and/or metastatic breast cancer: preclinical characterization and phase 1 trial results
Antibody drug conjugates (ADCs) with pyrrolobenzodiazepine (PBD) payloads are promising cancer therapeutics but are limited by toxicity. Here, the authors develop a HER2-targeted ADC (DHES0815A) with a reduced potency PBD payload that demonstrated promising preclinical efficacy and nonhuman primate tolerability, but culminated in a phase I clinical trial in patients with metastatic breast cancer which was terminated due to toxicity.
- Gail D. Lewis
- , Guangmin Li
- & Eunpi Cho
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Article
| Open AccessHigh resolution mapping of the tumor microenvironment using integrated single-cell, spatial and in situ analysis
The integration of single-cell and spatial data can provide a more comprehensive picture of the network of cells within the tumour microenvironment. Here the authors use a combination of single-cell and spatial technologies including 10x Xenium to characterise serial formalin-fixed, paraffin-embedded human breast cancer sections.
- Amanda Janesick
- , Robert Shelansky
- & Sarah E. B. Taylor
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Article
| Open AccessHigh-throughput deconvolution of 3D organoid dynamics at cellular resolution for cancer pharmacology with Cellos
Computational methods to analyse 3D organoids in high-throughput and with high cellular resolution remain scarce. Here, the authors propose Cellos, a high-throughput pipeline for 3D organoid segmentation using classical algorithms and a trained convolutional neural network.
- Patience Mukashyaka
- , Pooja Kumar
- & Jeffrey H. Chuang
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| Open AccessPyrotinib plus docetaxel as first-line treatment for HER2-positive metastatic breast cancer: the PANDORA phase II trial
HER2 targeted therapy combined with chemotherapy represents a standard approach for treating HER2-positive metastatic breast cancer (MBC). Here the authors report the results of a phase II trial of the small molecule tyrosine kinase inhibitor pyrotinib plus docetaxel as a first-line treatment for HER2-positive MBC.
- Yabing Zheng
- , Wen-Ming Cao
- & Xiaojia Wang
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| Open AccessEvaluation of circulating plasma proteins in breast cancer using Mendelian randomisation
Proteomics of blood samples is a promising avenue for cancer diagnosis. Here, the authors conduct Mendelian randomisation analysis of protein levels across multiple cohorts, and identify 5 proteins that show promise as biomarkers for the long-term risk of breast cancer, and as potential drug targets.
- Anders Mälarstig
- , Felix Grassmann
- & Åsa K. Hedman
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Article
| Open AccessGenetic separation of Brca1 functions reveal mutation-dependent Polθ vulnerabilities
Homologous recombination (HR) gene mutations are thought to be synthetic lethal with DNA polymerase theta (Polθ) inhibition. Here, the authors reveal that Polθ addiction is determined by the functional impact of gene mutations on DNA end resection activity.
- John J. Krais
- , David J. Glass
- & Neil Johnson
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Article
| Open AccessComprehensive genomic characterization of HER2-low and HER2-0 breast cancer
HER2-low breast cancer has recently emerged as a targetable subset of breast tumors, for which the molecular landscape remains incompletely understood. Here, the authors use genomic data from 1039 patients to unveil and compare the genomic landscape of HER2-low and HER2-0 breast cancer.
- Paolo Tarantino
- , Hersh Gupta
- & Nancy U. Lin
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| Open AccessGenomic profiling and pre-clinical modelling of breast cancer leptomeningeal metastasis reveals acquisition of a lobular-like phenotype
Breast cancer leptomeningeal metastasis is difficult to assess due to the site. Here, the authors assess cerebrospinal fluid cell-free DNA to show specific mutations present in leptomeningeal metastasis, and develop organoids of the disease.
- Amanda Fitzpatrick
- , Marjan Iravani
- & Clare M. Isacke
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Article
| Open AccessImmunological and clinicopathological features predict HER2-positive breast cancer prognosis in the neoadjuvant NeoALTTO and CALGB 40601 randomized trials
Neoadjuvant therapies with dual anti-HER2 blockade have proven effective in HER2+ breast cancer treatment. Here, the authors develop a score that integrates antigen receptor repertoire features and clinical parameters to predict prognosis after anti-HER2 neoadjuvant treatments.
- Mattia Rediti
- , Aranzazu Fernandez-Martinez
- & Christos Sotiriou
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Article
| Open AccessPaclitaxel plus carboplatin and durvalumab with or without oleclumab for women with previously untreated locally advanced or metastatic triple-negative breast cancer: the randomized SYNERGY phase I/II trial
Preclinical studies have shown that blockade of the CD73-adenosinergic pathway could improve anti-tumor immunity and response to other immune checkpoint inhibitors. Here the authors report the results of a randomized phase II trial of first-line durvalumab, paclitaxel and carboplatin with or without the anti-CD73 antibody oleclumab in patients with advanced triple-negative breast cancer.
- Laurence Buisseret
- , Delphine Loirat
- & Martine Piccart-Gebhart
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Article
| Open AccessInhibition of glycolysis-driven immunosuppression with a nano-assembly enhances response to immune checkpoint blockade therapy in triple negative breast cancer
A tumor cell-intrinsic hyperglycolytic state has been associated with immunosuppression and resistance to immune checkpoint blockade in triple negative breast cancer (TNBC). Here the authors describe an aptamer-based nanoassembly for tumor cell selective inhibition of glycolysis combined with bispecific immune checkpoint blockade, promoting anti-tumor immune responses in preclinical TNBC models.
- Xijiao Ren
- , Zhuo Cheng
- & Zhong Luo
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Article
| Open AccessToxic PARP trapping upon cAMP-induced DNA damage reinstates the efficacy of endocrine therapy and CDK4/6 inhibitors in treatment-refractory ER+ breast cancer
Resistance to standard of care (SOC) therapies reduces survival of estrogen receptor-positive (ER+) breast cancer patients. Here the authors show that SOC therapy downregulates the ER target phosphodiesterase 4D (PDE4D), causing DNA damage and cell death upon generation of functional BRCAness, and that combining SOC with inhibitors of PDE4D, EGFR or PARP1 overcomes SOC resistance irrespective of the BRCA1/2 status.
- Ozge Saatci
- , Metin Cetin
- & Ozgur Sahin
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Article
| Open AccessSingle-cell morphological and topological atlas reveals the ecosystem diversity of human breast cancer
Whole-slide images (WSI) and digital pathology are valuable approaches for the analysis of tumours and their microenvironments. Here, the authors present scMTOP, a framework to characterise tumour ecosystems and intercellular relationships at the single-cell level from WSIs, which they apply to breast cancer samples.
- Shen Zhao
- , De-Pin Chen
- & Zhi-Ming Shao
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Article
| Open AccessMutant p53 sustains serine-glycine synthesis and essential amino acids intake promoting breast cancer growth
Mutant p53 induces serine/glycine synthesis and essential amino acids intake. Under amino acid restriction, mutant p53 is stabilized and activates a transcriptional program that sustains a metabolic adaptive response promoting breast cancer cells growth
- Camilla Tombari
- , Alessandro Zannini
- & Giannino Del Sal
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Article
| Open AccessNeoadjuvant camrelizumab plus nab-paclitaxel and epirubicin in early triple-negative breast cancer: a single-arm phase II trial
Recent evidence suggests the feasibility of neoadjuvant immune checkpoint inhibitors plus chemotherapy-based therapy for patients with early triple-negative breast cancer (TNBC). Here the authors report the results of a single-arm phase II trial of neoadjuvant camrelizumab (anti-PD-1) plus nab-paclitaxel and epirubicin for early TNBC.
- Chengzheng Wang
- , Zhenzhen Liu
- & Min Yan
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Article
| Open AccessA randomized controlled trial testing a virtual program for Asian American women breast cancer survivors
Virtual support methods have been shown to be an effective aid in cancer survivorship. Here, the authors created a culturally tailored information and support system for Asian American breast cancer patients and showed these resources improved quality of life.
- Eun-Ok Im
- , Wonshik Chee
- & Jun J. Mao
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Article
| Open AccessDalpiciclib and pyrotinib in women with HER2-positive advanced breast cancer: a single-arm phase II trial
Dalpiciclib is a CDK4/6 inhibitor, recently approved for treatment in advanced breast cancer patients in China. Here, the authors report the results of a phase II trial investigating oral dalpiciclib (CDK4/6 inhibitor) and pyrotinib (pan-HER inhibitor) in patients with HER2-positive metastatic breast cancer.
- Min Yan
- , Limin Niu
- & Huajun Li
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Article
| Open AccessRepressed Blautia-acetate immunological axis underlies breast cancer progression promoted by chronic stress
Chronic stress can promote breast cancer progression. Here the authors show that a reduction in the levels of Blautia and its metabolite acetate contributes to chronic stress-promoted breast cancer progression, associated with decreased CD8 + T cell anti-tumor immunity.
- Ling Ye
- , Yuanlong Hou
- & Haiping Hao
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Article
| Open AccessCost-effectiveness requirements for implementing artificial intelligence technology in the Women’s UK Breast Cancer Screening service
AI technology has the potential to substitute a human reader to aid services struggling to recruit staff or meet patient demand. Here, the authors show that the technology is a viable and potentially cost-effective strategy for use in the NHS.
- Armando Vargas-Palacios
- , Nisha Sharma
- & Gurdeep S. Sagoo
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Article
| Open AccessDeep learning-enabled realistic virtual histology with ultraviolet photoacoustic remote sensing microscopy
Oncologic tumour resection is not fully accurate. Here the authors report a label-free virtual histological imaging method based on a non-contact, reflection-mode ultraviolet photoacoustic remote sensing and scattering microscope, combined with unsupervised deep learning using a cycle-consistent GAN.
- Matthew T. Martell
- , Nathaniel J. M. Haven
- & Roger J. Zemp
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Article
| Open AccessPerformance of tumour microenvironment deconvolution methods in breast cancer using single-cell simulated bulk mixtures
Multiple computational approaches have been developed for the deconvolution of cells in the tumour microenvironment (TME) using bulk RNA-seq data. Here, the authors use breast cancer single-cell RNA-seq data to produce simulated bulk data, with which they compare the performance of nine TME deconvolution methods.
- Khoa A. Tran
- , Venkateswar Addala
- & Nicola Waddell