ArticleCurrent medicinal chemistry2014
P38 MAPK contributes to resistance and invasiveness of HER2- overexpressing breast cancer.
Article in Current medicinal chemistry, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 36 papers.
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Who cites it
36 citing papers in PubMed, 54 citations in OpenAlex.
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- Targeting the MAPK signaling pathway: implications and prospects of flavonoids in 3P medicine as modulators of cancer cell plasticity and therapeutic resistance in breast cancer patients.The EPMA journal · 2025Article
- Hyaluronan: An Architect and Integrator for Cancer and Neural Diseases.International journal of molecular sciences · 2025Review
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- HER2-Positive Breast Cancer Treatment and Resistance.Advances in experimental medicine and biology · 2025Review
- HER2 phosphorylation induced by TGF-β promotes mammary morphogenesis and breast cancer progression.The Journal of cell biology · 2024Article
- Therapeutic and pharmacological efficacy of plant-derived bioactive compounds in targeting breast cancer.American journal of translational research · 2024Review
- Generation and Characterization of Trastuzumab/Pertuzumab-Resistant HER2-Positive Breast Cancer Cell Lines.International journal of molecular sciences · 2023Article
- GDNF family receptor alpha-like antagonist antibody alleviates chemotherapy-induced cachexia in melanoma-bearing mice.Journal of cachexia, sarcopenia and muscle · 2023Article
- Transcriptome of Lung Cancer Cells Resistant to the Cytotoxic Activity of Macrophages.Doklady. Biochemistry and biophysics · 2022Article
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- Pathophysiological role of growth differentiation factor 15 (GDF15) in obesity, cancer, and cachexia.Cytokine & growth factor reviews · 2022Review
- Bone morphogenetic proteins, activins, and growth and differentiation factors in tumor immunology and immunotherapy resistance.Frontiers in immunology · 2022Review
- The role of MAPK11/12/13/14 (p38 MAPK) protein in dopamine agonist-resistant prolactinomas.BMC endocrine disorders · 2021Article
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- Pan-cancer analysis of pathway-based gene expression pattern at the individual level reveals biomarkers of clinical prognosis.Cell reports methods · 2021Article
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Authors and funding
6 authors at 1 institution in 1 country.
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Abstract
Intrinsic or acquired resistance to the HER2-targeted therapy trastuzumab is a clinical concern in the treatment of patients with HER2-over-expressing metastatic breast cancers. We demonstrate here that multiple models of intrinsic and acquired resistance exhibit increased phosphorylation of p38 MAPK. Kinase inhibition of p38 rescued trastuzumab sensitivity in cells with acquired resistance. In addition, knockdown of p38 increased sensitivity to trastuzumab in an intrinsically resistant cell line. We previously reported that expression of growth differentiation factor 15 (GDF15) is increased in trastuzumab-resistant HER2-overexpressing breast cancer cells. In this study, we found that exogenous GDF15 or stable overexpression of GDF15 stimulated p38 phosphorylation in HER2-positive cells, suggesting a possible mechanism by which p38 is activated in resistant cells.GDF15 stable clones showed significantly increased invasiveness, which was rescued by p38 kinase inhibition, suggesting that p38 plays a role in the pro-invasive phenotype conferred by GDF15. Importantly, immunohistochemical analysis of a breast tumor tissue array indicated a significant (p=0.0053) correlation between HER2 and phosphorylated p38 specifically in GDF15-positive tissues. Our results suggest that p38 signaling drives trastuzumab resistance and invasiveness in HER2-overexpressing breast cancer. Upstream growth factor signals that have previously been implicated in trastuzumab resistance, such as GDF15, may contribute to the increased phosphorylation of p38 found in resistant cells.
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