ArticleCell systems2018
Microenvironment-Mediated Mechanisms of Resistance to HER2 Inhibitors Differ between HER2+ Breast Cancer Subtypes.
Open access · hybridAbstract read
In one paragraph
Article in Cell systems, 2018. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 60 papers.
0numbers the graph read from it
0cells of the map it votes in
60citing papers in PubMed
4.3field-weighted citation impact, top 4% of its field
What it found
Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.
The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.
Who cites it
60 citing papers in PubMed, 99 citations in OpenAlex.
- S-nitrosylated COX-2 is a microenvironment-regulated breast cancer cell biomarker of mesenchymal phenotypes.Experimental cell research · 2026Article
- Tumor-Intrinsic PD-1 Regulatory Network Drives Lapatinib Resistance in HER2⁺ Breast Cancer: An Integrative Bioinformatics Analysis.Asian Pacific journal of cancer prevention : APJCP · 2026Article
- Treatment resistance to platinum-based chemotherapy in lung and ovarian cancer is driven by a targetable TGFβ senescent secretome.Nature aging · 2026Article
- Precision targeting of the SASP in cancer therapy.Nature aging · 2026Article
- MicroRNA-mediated modulation of cancer-associated fibroblasts in HER2-positive breast tumor microenvironment: a comprehensive review.Discover oncology · 2026Review
- Growth factors maintain intratumoral heterogeneity and drive therapeutic resistance in triple-negative breast cancer.Cell reports · 2026Article
- Identification of senescence-associated drivers of tumour growth and progression using a novel microarray platform.bioRxiv : the preprint server for biology · 2025Article
- Breast cancer cell coculture induces normal lung fibroblast transition to CAFs, promoting tumor cell dormancy and therapy resistance.Proceedings of the National Academy of Sciences of the United States of America · 2025Article
- Proximity Ligation Assay: From a Foundational Principle to a Versatile Platform for Molecular and Translational Research.Biomolecules · 2025Review
- Advancing Breast Cancer Treatment: The Role of Immunotherapy and Cancer Vaccines in Overcoming Therapeutic Challenges.Vaccines · 2025Review
- Harnessing the tumor microenvironment: targeted cancer therapies through modulation of epithelial-mesenchymal transition.Journal of hematology & oncology · 2025Review
- Rational Design of HER2-Targeted Combination Therapies to Reverse Drug Resistance in Fibroblast-Protected HER2+ Breast Cancer Cells.Cellular and molecular bioengineering · 2024Article
- Therapeutic advances of targeting receptor tyrosine kinases in cancer.Signal transduction and targeted therapy · 2024Review
- Depicting Biomarkers for HER2-Inhibitor Resistance: Implication for Therapy in HER2-Positive Breast Cancer.Cancers · 2024Review
- A prospective study of HER3 expression pre and post neoadjuvant therapy of different breast cancer subtypes: implications for HER3 imaging therapy guidance.Breast cancer research : BCR · 2024Article
- Quantitative systems pharmacology modeling of HER2-positive metastatic breast cancer for translational efficacy evaluation and combination assessment across therapeutic modalities.Acta pharmacologica Sinica · 2024Article
- Bridging systems biology and tissue engineering: Unleashing the full potential of complex 3DBiophysics reviews · 2024Review
- Integrating single-cell and bulk RNA sequencing data unveils antigen presentation and process-related CAFS and establishes a predictive signature in prostate cancer.Journal of translational medicine · 2024Article
- Functional delineation of the luminal epithelial microenvironment in breast using cell-based screening in combinatorial microenvironments.Cellular signalling · 2024Article
- Oncofetal reprogramming in tumor development and progression: novel insights into cancer therapy.MedComm · 2023Review
Corrections and comments
- Commented on by
Authors and funding
18 authors at 4 institutions in 1 country.
Spencer S WatsonDepartment of Biomedical Engineering, Knight Cancer Institute, OHSU Center for Spatial Systems Biomedicine, Oregon Health and Science University, 3181 SW Sam Jackson Park Road, Portland, OR 97239, USA.
Mark DaneDepartment of Biomedical Engineering, Knight Cancer Institute, OHSU Center for Spatial Systems Biomedicine, Oregon Health and Science University, 3181 SW Sam Jackson Park Road, Portland, OR 97239, USA.
Koei ChinDepartment of Biomedical Engineering, Knight Cancer Institute, OHSU Center for Spatial Systems Biomedicine, Oregon Health and Science University, 3181 SW Sam Jackson Park Road, Portland, OR 97239, USA.
Zuzana TatarovaDepartment of Biomedical Engineering, Knight Cancer Institute, OHSU Center for Spatial Systems Biomedicine, Oregon Health and Science University, 3181 SW Sam Jackson Park Road, Portland, OR 97239, USA.
Moqing LiuDepartment of Biomedical Engineering, Knight Cancer Institute, OHSU Center for Spatial Systems Biomedicine, Oregon Health and Science University, 3181 SW Sam Jackson Park Road, Portland, OR 97239, USA.
Tiera LibyDepartment of Biomedical Engineering, Knight Cancer Institute, OHSU Center for Spatial Systems Biomedicine, Oregon Health and Science University, 3181 SW Sam Jackson Park Road, Portland, OR 97239, USA.
Wallace ThompsonDepartment of Biomedical Engineering, Knight Cancer Institute, OHSU Center for Spatial Systems Biomedicine, Oregon Health and Science University, 3181 SW Sam Jackson Park Road, Portland, OR 97239, USA.
Rebecca SmithDepartment of Biomedical Engineering, Knight Cancer Institute, OHSU Center for Spatial Systems Biomedicine, Oregon Health and Science University, 3181 SW Sam Jackson Park Road, Portland, OR 97239, USA.
Michel NederlofDepartment of Biomedical Engineering, Knight Cancer Institute, OHSU Center for Spatial Systems Biomedicine, Oregon Health and Science University, 3181 SW Sam Jackson Park Road, Portland, OR 97239, USA; Quantitative Imaging Systems LLC, 1410 NW Kearney Street, #1114, Portland, OR 97209, USA.
Elmar BucherDepartment of Biomedical Engineering, Knight Cancer Institute, OHSU Center for Spatial Systems Biomedicine, Oregon Health and Science University, 3181 SW Sam Jackson Park Road, Portland, OR 97239, USA.
David KilburnDepartment of Biomedical Engineering, Knight Cancer Institute, OHSU Center for Spatial Systems Biomedicine, Oregon Health and Science University, 3181 SW Sam Jackson Park Road, Portland, OR 97239, USA.
Matthew WhitmanDepartment of Radiology, Brigham & Women's Hospital, Harvard Medical School, 75 Francis St, Boston, MA 02115, USA.
Damir SudarDepartment of Biomedical Engineering, Knight Cancer Institute, OHSU Center for Spatial Systems Biomedicine, Oregon Health and Science University, 3181 SW Sam Jackson Park Road, Portland, OR 97239, USA; Quantitative Imaging Systems LLC, 1410 NW Kearney Street, #1114, Portland, OR 97209, USA.
Gordon B MillsDepartment of Systems Biology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, USA.
Laura M HeiserDepartment of Biomedical Engineering, Knight Cancer Institute, OHSU Center for Spatial Systems Biomedicine, Oregon Health and Science University, 3181 SW Sam Jackson Park Road, Portland, OR 97239, USA.
Oliver JonasDepartment of Radiology, Brigham & Women's Hospital, Harvard Medical School, 75 Francis St, Boston, MA 02115, USA.
Joe W GrayDepartment of Biomedical Engineering, Knight Cancer Institute, OHSU Center for Spatial Systems Biomedicine, Oregon Health and Science University, 3181 SW Sam Jackson Park Road, Portland, OR 97239, USA. Electronic address: grayjo@ohsu.edu.
James E KorkolaDepartment of Biomedical Engineering, Knight Cancer Institute, OHSU Center for Spatial Systems Biomedicine, Oregon Health and Science University, 3181 SW Sam Jackson Park Road, Portland, OR 97239, USA. Electronic address: korkola@ohsu.edu.
Oregon Health & Science University · USBrigham and Women's Hospital · USHarvard University · USThe University of Texas MD Anderson Cancer Center · US
Funding
Tumor Evolution and Metastasis ProgramP30CA016672 · NCI · UNIVERSITY OF TX MD ANDERSON CAN CTR · PI Scott Kopetz · 1985 to 2026
$290.8MUnderstanding the origins of rapid recurrence of pancreatic cancer after resectionP30CA069533 · NCI · OREGON HEALTH & SCIENCE UNIVERSITY · PI Luiz Eduardo Bertassoni · 1997 to 2026
$60.5MProteomics CoreP30EY010572 · NEI · OREGON HEALTH & SCIENCE UNIVERSITY · PI TED S ACOTT · 1995 to 2026
$19.4MOutreachU54HG008100 · NHGRI · OREGON HEALTH & SCIENCE UNIVERSITY · PI GRAY, JOE W., HEISER, LAURA MADELINE · 2014 to 2019
$10.5MIntratumor heterogeneity underlying treatment resistance in HER2+ breast tumorsU01CA195469 · NCI · DANA-FARBER CANCER INST · PI GRAY, JOE W., MICHOR, FRANZISKA · 2015 to 2019
$3.3MImplantable microdevices with integrated optical imaging for high-throughput in situ tumor response and drug sensitivity measurementR37CA224144 · NCI · BRIGHAM AND WOMEN'S HOSPITAL · PI JONAS, OLIVER · 2018 to 2023
$2.4MIn Situ characterization and manipulation of tumor immune cell metabolomics using implantable microdevicesR01CA223150 · NCI · BRIGHAM AND WOMEN'S HOSPITAL · PI JONAS, OLIVER · 2018 to 2022
$1.9MLTQ Orbitrap VelosS10OD012246 · OD · OREGON HEALTH & SCIENCE UNIVERSITY · PI DAVID, LARRY L · 2012 to 2012
$854kInterrogating Mechanisms of HER2+ Breast Cancer Drug Resistance Using Microenvironment MicroarraysF31CA200322 · NCI · OREGON HEALTH & SCIENCE UNIVERSITY · PI WATSON, SPENCER STUART · 2016 to 2017
$72kNCI NIH HHS F31 CA200322NCI NIH HHS P30 CA016672NCI NIH HHS P30 CA069533NCI NIH HHS R01 CA223150NCI NIH HHS R37 CA224144NCI NIH HHS U01 CA195469NEI NIH HHS P30 EY010572NHGRI NIH HHS U54 HG008100NIH HHS S10 OD012246
Abstract
Extrinsic signals are implicated in breast cancer resistance to HER2-targeted tyrosine kinase inhibitors (TKIs). To examine how microenvironmental signals influence resistance, we monitored TKI-treated breast cancer cell lines grown on microenvironment microarrays composed of printed extracellular matrix proteins supplemented with soluble proteins. We tested ∼2,500 combinations of 56 soluble and 46 matrix microenvironmental proteins on basal-like HER2+ (HER2E) or luminal-like HER2+ (L-HER2+) cells treated with the TKIs lapatinib or neratinib. In HER2E cells, hepatocyte growth factor, a ligand for MET, induced resistance that could be reversed with crizotinib, an inhibitor of MET. In L-HER2+ cells, neuregulin1-β1 (NRG1β), a ligand for HER3, induced resistance that could be reversed with pertuzumab, an inhibitor of HER2-HER3 heterodimerization. The subtype-specific responses were also observed in 3D cultures and murine xenografts. These results, along with bioinformatic pathway analysis and siRNA knockdown experiments, suggest different mechanisms of resistance specific to each HER2+ subtype: MET signaling for HER2E and HER2-HER3 heterodimerization for L-HER2+ cells.
Indexed as
AnimalsAntineoplastic AgentsBreast NeoplasmsCell Line, TumorDatabases, GeneticDrug Resistance, NeoplasmEnzyme InhibitorsErb-b2 Receptor Tyrosine KinasesFemaleGene Expression Regulation, NeoplasticGenes, erbB-2High-Throughput Screening AssaysHumansLapatinibMCF-7 CellsMiceAntineoplastic AgentsEnzyme InhibitorsErb-b2 Receptor Tyrosine KinasesLapatinibneratinibProtein Kinase InhibitorsProtein-Tyrosine KinasesProto-Oncogene Proteins c-metQuinazolinesQuinolinesReceptor, ErbB-3crizotinibdrug resistanceHER2+ breast cancer subtypesHER3HGFlapatinibmicroenvironmentneratinibNRG1βpertuzumab
Identifiers
What OpenQuestion holds
Textmetadata
LicenceCC BY
Read underepoch 390
Registered trials
None linked
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.