P27kip1 Down-Regulation Is Associated with Trastuzumab Resistance in Breast Cancer Cells
Open accessAbstract
Trastuzumab (Herceptin) is a recombinant humanized monoclonal antibody directed against HER-2. The objective response rate to trastuzumab monotherapy is 12-34% for a median duration of 9 months, by which point most patients become resistant to treatment. We created two trastuzumab-resistant (TR) pools from the SKBR3 HER-2-overexpressing breast cancer cell line to study the mechanisms by which breast cancer cells escape trastuzumab-mediated growth inhibition. Both pools maintained her-2 gene amplification and protein overexpression. Resistant cells demonstrated a higher S-phase fraction by flow cytometry and a faster doubling time of 24-36 h compared with 72 h for parental cells. The cyclin-dependent kinase inhibitor p27(kip1) was decreased in TR cells, and cyclin-dependent kinase 2 activity was increased. Importantly, exogenous addition of p27(kip1) increased trastuzumab sensitivity. Additionally, resistant cells displayed heightened sensitivity to the proteasome inhibitor MG132, which induced p27(kip1) expression. Thus, we propose that trastuzumab resistance may be associated with decreased p27(kip1) levels and may be susceptible to treatments that induce p27(kip1) expression.
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Downregulation of the Cdk inhibitor p27KIP1 and a resulting increase in Cdk activity has been associated with trastuzumab resistance.
“Downregulation of the Cdk inhibitor p27KIP1 and a resulting increase in Cdk activity has also been associated with trastuzumab resistance (Nahta et al., 2004; Yakes et al., 2002).”
From ERBB Receptors: From Oncogene Discovery to Basic Science to Mechanism-Based Cancer Therapeutics (2014) · cites this paper as Nahta et al., 2004
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References 18 · Cited by 298
- Authors
- Nahta, R., Takahashi, T., Ueno, N. T., Hung, M.-C., & Esteva, F. J.
- Affiliations
- 1Breast Medical Oncology, Departments of
- The University of Texas MD Anderson Cancer Center (US)
- 2Molecular and Cellular Oncology, and
- Venue
- Cancer Research
- Published
- 2004-06-01
- Volume
- 64
- Issue
- 11
- Pages
- 3981-3986
- ISSN
- 0008-5472 (ISSN-L)
- 1538-7445
- OpenAlex
- W1967226516
- Cited by
- 298
- References
- 18
- Citations by year
- 2026: 1 · 2025: 2 · 2024: 5 · 2023: 7 · 2022: 5 · 2021: 8 · 2020: 10 · 2019: 5 · 2018: 8 · 2017: 11 · 2016: 11 · 2015: 16 · 2014: 13 · 2013: 13 · 2012: 23
- FWCI
- 9.11
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Cancer Research (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Cancer Institute (K23 CA82119, P01CA099031, K23CA082119)
- Topics
- Health Sciences › Medicine › Oncology › HER2/EGFR in Cancer Research
- Health Sciences › Medicine › Oncology › Cancer-related Molecular Pathways
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Lung Cancer Treatments and Mutations
- Keywords
- trastuzumab resistance, p27, breast cancer, HER2 overexpression, SK-BR-3 cells, CDK2, proteasome inhibition, MG132, S-phase fraction, cell doubling time, drug resistance mechanisms
- MeSH terms
- Trastuzumab, Antibodies, Monoclonal, Antineoplastic Agents, Breast Neoplasms, Cell Division, Humans, Down-Regulation, Gene Expression Regulation, Neoplastic, Cell Cycle Proteins, Drug Resistance, Neoplasm, Tumor Suppressor Proteins, CDC2-CDC28 Kinases, Cell Line, Tumor, Cyclin-Dependent Kinase Inhibitor p27, Cyclin-Dependent Kinase 2, Antibodies, Monoclonal, Humanized
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