ArticleOncotarget2015
Hypoxia/HIF1α induces lapatinib resistance in ERBB2-positive breast cancer cells via regulation of DUSP2.
Article in Oncotarget, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 29 papers.
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Who cites it
29 citing papers in PubMed, 44 citations in OpenAlex.
- Expression characteristics of dual-specificity phosphatase 2 and hypoxia-inducible factor-1α in acute kidney injury and preliminary study of the effect of dual-specificity phosphatase 2 on HK-2 cells.Experimental physiology · 2025Article
- Dual-Specificity Protein Phosphatases Targeting Extracellular Signal-Regulated Kinases: Friends or Foes in the Biology of Cancer?International journal of molecular sciences · 2025Review
- Histotripsy-Focused Ultrasound Treatment Abrogates Tumor Hypoxia Responses and Stimulates Antitumor Immune Responses in Melanoma.Molecular cancer therapeutics · 2025Article
- Hypoxia signaling in the adipose tissue.Journal of molecular cell biology · 2025Review
- The signature of extracellular vesicles in hypoxic breast cancer and their therapeutic engineering.Cell communication and signaling : CCS · 2024Review
- Dual-Specificity Phosphatases in Regulation of Tumor-Associated Macrophage Activity.International journal of molecular sciences · 2023Review
- The SKA3-DUSP2 Axis Promotes Gastric Cancer Tumorigenesis and Epithelial-Mesenchymal Transition by Activating the MAPK/ERK Pathway.Frontiers in pharmacology · 2022Article
- Dual-specificity phosphatases: therapeutic targets in cancer therapy resistance.Journal of cancer research and clinical oncology · 2022Review
- miR‑212 promotes renal interstitial fibrosis by inhibiting hypoxia‑inducible factor 1‑α inhibitor.Molecular medicine reports · 2021Article
- HIF1α Regulates IL17 Signaling Pathway Influencing Sensitivity of Taxane-Based Chemotherapy for Breast Cancer.Frontiers in cell and developmental biology · 2021Article
- Upregulation of HIF1-α via an NF-κB/COX2 pathway confers proliferative dominance of HER2-negative ductal carcinoma in situ cells in response to inflammatory stimuli.Neoplasia (New York, N.Y.) · 2020Article
- Three dimensional engineered models to study hypoxia biology in breast cancer.Cancer letters · 2020Review
- miR-106a Reduces 5-Fluorouracil (5-FU) Sensitivity of Colorectal Cancer by Targeting Dual-Specificity Phosphatases 2 (DUSP2).Medical science monitor : international medical journal of experimental and clinical research · 2018Article
- Article
- Intravital Imaging to Monitor Therapeutic Response in Moving Hypoxic Regions Resistant to PI3K Pathway Targeting in Pancreatic Cancer.Cell reports · 2018Article
- Differential expression of DUSP2 in left- and right-sided colon cancer is associated with poor prognosis in colorectal cancer.Oncology letters · 2018Article
- Investigation of hypoxia networks in ovarian cancer via bioinformatics analysis.Journal of ovarian research · 2018Article
- Targeting signaling and apoptotic pathways involved in chemotherapeutic drug-resistance of hematopoietic cells.Oncotarget · 2017Article
- MEK inhibitors induce Akt activation and drug resistance by suppressing negative feedback ERK-mediated HER2 phosphorylation at Thr701.Molecular oncology · 2017Article
- Targeting Tumor Adaption to Chronic Hypoxia: Implications for Drug Resistance, and How It Can Be Overcome.International journal of molecular sciences · 2017Review
Corrections and comments
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Authors and funding
2 authors at 1 institution in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
ERBB2/HER2 belongs to the EGFR-family of receptor tyrosine kinases and its overexpression can promote tumor progression. Breast cancer patients with ERBB2 amplifications are currently treated with lapatinib, a small-molecule kinase inhibitor that specifically blocks EGFR/ERBB2 signaling. Here, we show that hypoxia, via HIF-1, induces resistance to lapatinib-mediated effects in ERBB2-expressing mammary epithelial and ERBB2-positive breast cancer cells. Lapatinib-mediated growth inhibition and apoptosis in three-dimensional (3D) cultures are decreased under hypoxic conditions. Hypoxia can maintain activation of signaling pathways downstream from ERBB2 including AKT and ERK in the presence of lapatinib. HIF-1 is both required and sufficient to induce lapatinib resistance as overexpression of stable HIF-1 in ERBB2-expressing cells blocks lapatinib-mediated effects and maintains ERBB2-downstream signaling under normoxic conditions. Under hypoxia, activation of ERK signaling is required for lapatinib resistance as treatment with MEK inhibitor trametinib reverses hypoxia-mediated lapatinib resistance. HIF-1 can bypass the lapatinib-treated inhibition of the ERK pathway via inhibition of the dual-specificity phosphatase 2 (DUSP2). Indeed, overexpression of DUSP2 in ErbB2-positve breast cancer cells reverses hypoxia-mediated lapatinib resistance. Thus, our results provide rationale for therapeutic evaluation of the treatment of hypoxic ERBB2 expressing breast tumors with a combination of lapatinib and MEK inhibitors.
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