ArticleClinical cancer research : an official journal of the American Association for Cancer Research2009
Protein kinase A activation confers resistance to trastuzumab in human breast cancer cell lines.
Article in Clinical cancer research : an official journal of the American Association for Cancer Research, 2009. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 38 papers.
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Who cites it
38 citing papers in PubMed, 52 citations in OpenAlex.
- A phase I/II prospective, single arm trial of gefitinib, trastuzumab, and docetaxel in patients with stage IV HER-2 positive metastatic breast cancer.Breast cancer research and treatment · 2012Trial
- Oncogenic role and potential mechanisms of MYO1B in breast cancer.In vitro cellular & developmental biology. Animal · 2026Article
- A Holistic Review of Oncological Drug Targets and Trajectories of Resistance in Cancer Therapy.Oncology research · 2026Review
- Molecular Subtypes and Risk Prediction Model Based on Malignant Cell Differentiation Trajectories in Breast Cancer.Journal of cellular and molecular medicine · 2025Article
- Article
- IKKα promotes lung adenocarcinoma growth through ERK signaling activation via DARPP-32-mediated inhibition of PP1 activity.NPJ precision oncology · 2023Article
- Targeting tumor innervation: premises, promises, and challenges.Cell death discovery · 2022Review
- GPharmacological reviews · 2021Review
- Mechanisms Supporting the Use of Beta-Blockers for the Management of Breast Cancer Bone Metastasis.Cancers · 2021Review
- Neurobiology of Cancer: Introduction of New Drugs in the Treatment and Prevention of Cancer.International journal of molecular sciences · 2021Review
- PP1, PKA and DARPP-32 in breast cancer: A retrospective assessment of protein and mRNA expression.Journal of cellular and molecular medicine · 2021Article
- High-Throughput Assessment of Kinome-wide Activation States.Cell systems · 2019Article
- ANKRD44 Gene Silencing: A Putative Role in Trastuzumab Resistance in Her2-Like Breast Cancer.Frontiers in oncology · 2019Article
- t-Darpp Activates IGF-1R Signaling to Regulate Glucose Metabolism in Trastuzumab-Resistant Breast Cancer Cells.Clinical cancer research : an official journal of the American Association for Cancer Research · 2018Article
- t-Darpp stimulates protein kinase A activity by forming a complex with its RI regulatory subunit.Cellular signalling · 2017Article
- Pathway-based discovery of genetic interactions in breast cancer.PLoS genetics · 2017Article
- t-Darpp is an elongated monomer that binds calcium and is phosphorylated by cyclin-dependent kinases 1 and 5.FEBS open bio · 2017Article
- FSIP1 binds HER2 directly to regulate breast cancer growth and invasiveness.Proceedings of the National Academy of Sciences of the United States of America · 2017Article
- Cytoprotective effect of neuropeptides on cancer stem cells: vasoactive intestinal peptide-induced antiapoptotic signaling.Cell death & disease · 2017Article
- Loss of phosphodiesterase 4D mediates acquired triapine resistance via Epac-Rap1-Integrin signaling.Oncotarget · 2016Article
Corrections and comments
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Authors and funding
5 authors at 1 institution in 1 country.
Funding
Abstract
purposeTrastuzumab is a monoclonal antibody targeted to the Her2 receptor and approved for treatment of Her2-positive breast cancer. Among patients who initially respond to trastuzumab therapy, resistance typically arises within 1 year. BT/Her(R) cells are trastuzumab-resistant variants of Her2-positive BT474 breast cancer cells. The salient feature of BT/Her(R) cells is failure to downregulate phosphoinositide 3-kinase/Akt signaling on trastuzumab binding. The current work addresses the mechanism of sustained signaling in BT/Her(R) cells, focusing on the protein kinase A (PKA) pathway. EXPERIMENTAL
designWe performed microarray analysis on BT/Her(R) and BT474 cell lines to identify genes that were upregulated or downregulated in trastuzumab-resistant cells. Specific genes in the PKA pathway were quantified using reverse transcription-PCR and Western hybridization. Small interfering RNA transfection was used to determine the effects of gene knockdown on cellular response to trastuzumab. Electrophoretic mobility shift assays were used to measure cyclic AMP-responsive element binding activity under defined conditions. Immunohistochemistry was used to analyze protein expression in clinical samples.
resultsBT/Her(R) cells had elevated PKA signaling activity and several genes in the PKA regulatory network had altered expression in these cells. Downregulation of one such gene, the PKA-RIIalpha regulatory subunit, conferred partial trastuzumab resistance in Her2-positive BT474 and SK-Br-3 cell lines. Forskolin activation of PKA also produced significant protection against trastuzumab-mediated Akt dephosphorylation. In patient samples, PKA signaling appeared to be enhanced in residual disease remaining after trastuzumab-containing neoadjuvant therapy.
conclusionsActivation of PKA signaling may be one mechanism contributing to trastuzumab resistance in Her2-positive breast cancer. We propose a molecular model by which PKA confers its effects.
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