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Cited by 104Ubiquitin and proteasome pathwaysProtease and Inhibitor MechanismsHER2/EGFR in Cancer Research

Differential cellular and molecular effects of bortezomib, a proteasome inhibitor, in human breast cancer cells

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Codony-Servat, Jordi, Tapia, Maria A., Bosch, Marta, Oliva, Cristina, Domingo-Domenech, Josep, Mellado, Begoña, Rolfe, Mark, Ross, Jeffrey S. +3 more·2006·Molecular Cancer Therapeutics
DOI 10.1158/1535-7163.mct-05-0147
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Abstract

The cellular and molecular effects of the proteasome inhibitor bortezomib on breast cancer cells are as yet poorly characterized. Here, in a panel of six breast cancer cell lines, bortezomib reduced viability in a concentration-dependent, time-dependent, and cell line–dependent manner. Proteasome activity was relatively high in two of the three more resistant cell lines. No relationship was observed between bortezomib effects on cell viability and expression/phosphorylation of HER-2, epidermal growth factor receptor (EGFR), AKT, or extracellular signal-regulated kinase 1/2 (ERK1/2). Molecular effects of bortezomib were further studied in SK-BR-3 and BT-474 cells because they share expression of EGFR and overexpression of HER-2 while, in contrast, SK-BR-3 cells were 200-fold more sensitive to this agent. Proteasome activity was inhibited to a similar extent in the two cell lines, and known proteasome substrates accumulated similarly. In SK-BR-3 cells, a marked inhibition of EGFR, HER-2, and AKT phosphorylation was observed at a clinically relevant concentration of bortezomib. In contrast, phosphorylation of Raf/mitogen-activated protein kinase kinase 1/2 (MEK 1/2)/ERK1/2 increased by bortezomib. In BT-474 cells, the effects were much less pronounced. Treatment of SK-BR-3 cells with bortezomib combined with pharmacologic inhibitors of EGFR, phosphatidylinositol 3′-kinase, or MEK resulted in modest or no enhancement of the effects on cell viability. Collectively, these results show that bortezomib has differential cellular and molecular effects in human breast cancer cells. The bortezomib-observed effects on signaling transduction molecules might be relevant to help to design mechanistic-based combination treatments. [Mol Cancer Ther 2006;5(3):665–75]

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  • Previous studies across multiple tumor types have reported variable effects of bortezomib on MAPK signaling.

    “Previous studies across multiple tumor types including breast cancer, plasma cell leukemia, or multiple myeloma have reported variable effects of bortezomib on MAPK signaling [[340], [341], [342]], underscoring the context-dependent nature of this interaction.”

    From HIF inhibition: Current strategies and clinical challenges (2026) · cites this paper as [340]

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Authors
Codony-Servat, J., Tapia, M. A., Bosch, M., Oliva, C., Domingo-Domenech, J., Mellado, B., Rolfe, M., Ross, J. S., Gascon, P., Rovira, A., & Albanell, J.
Affiliations
  • 1Laboratory of Experimental Oncology, Medical Oncology Department, Institut d'Investigacions Biomediques August Pi i Sunyer, Hospital Clinic i Provincial de Barcelona, Barcelona, Spain;
  • Hospital Clínic de Barcelona (ES)
  • Takeda Oncology (United States) (US)
  • Albany Medical College (US)
ORCID
Venue
Molecular Cancer Therapeutics
Publisher
American Association for Cancer Research (AACR)
Published
2006-03-01
Volume
5
Issue
3
Pages
665-675
ISSN
  • 1535-7163 (ISSN-L)
  • 1538-8514
DOI
10.1158/1535-7163.mct-05-0147
OpenAlex
W2134657928
Cited by
104
References
2
Citations by year
2026: 1 · 2025: 2 · 2024: 3 · 2023: 3 · 2022: 2 · 2021: 1 · 2020: 2 · 2019: 6 · 2018: 2 · 2017: 4 · 2016: 4 · 2015: 4 · 2014: 11 · 2013: 7 · 2012: 4
FWCI
4.35
Type
journal article
Language
en
Open access
Locations
  • Molecular Cancer Therapeutics (publishedVersion)
  • PubMed (publishedVersion)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ubiquitin and proteasome pathways
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Protease and Inhibitor Mechanisms
  • Health Sciences › Medicine › Oncology › HER2/EGFR in Cancer Research
Keywords
bortezomib, proteasome inhibitors, breast cancer, cell viability, proteasome activity, HER2, EGFR, Akt phosphorylation, ERK1/2 phosphorylation, MEK, MAPK/ERK pathway, SK-BR-3 cells, BT474 cells, drug resistance, combination therapy, phosphatidylinositol 3-kinase
MeSH terms
Bortezomib, Boronic Acids, Breast Neoplasms, Cell Survival, Enzyme Activation, Female, Humans, Phosphoprotein Phosphatases, Phosphorylation, Pyrazines, Cysteine Proteinase Inhibitors, Protein Tyrosine Phosphatases, Protein Serine-Threonine Kinases, Immediate-Early Proteins, Receptor, ErbB-2, Erb-b2 Receptor Tyrosine Kinases, Cell Cycle Proteins, Drug Resistance, Neoplasm, Mitogen-Activated Protein Kinase 1, Receptor Protein-Tyrosine Kinases, MAP Kinase Kinase Kinases, Cell Line, Tumor, raf Kinases, MAP Kinase Kinase 4, Proto-Oncogene Proteins c-akt, Dual Specificity Phosphatase 1, Protein Phosphatase 1, Proteasome Inhibitors, ErbB Receptors

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