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Lapatinib–induced NF-kappaB activation sensitizes triple-negative breast cancer cells to proteasome inhibitors
- Source :
- Breast Cancer Research : BCR
- Publication Year :
- 2013
- Publisher :
- Springer Science and Business Media LLC, 2013.
-
Abstract
- Introduction Triple-negative breast cancer (TNBC), a subtype of breast cancer with negative expressions of estrogen receptor, progesterone receptor, and human epidermal growth factor receptor 2 (HER2), is frequently diagnosed in younger women and has poor prognosis for disease-free and overall survival. Due to the lack of known oncogenic drivers for TNBC proliferation, clinical benefit from currently available targeted therapies is limited, and new therapeutic strategies are urgently needed. Methods Triple-negative breast cancer cell lines were treated with proteasome inhibitors in combination with lapatinib (a dual epidermal growth factor receptor (EGFR)/HER2 tyrosine kinase inhibitor). Their in vitro and in vivo viability was examined by MTT assay, clonogenic analysis, and orthotopic xenograft mice model. Luciferase reporter gene, immunoblot, and RT-qPCR, immunoprecipitation assays were used to investigate the molecular mechanisms of action. Results Our data showed that nuclear factor (NF)-κB activation was elicited by lapatinib, independent of EGFR/HER2 inhibition, in TNBCs. Lapatinib-induced constitutive activation of NF-κB involved Src family kinase (SFK)-dependent p65 and IκBα phosphorylations, and rendered these cells more vulnerable to NF-κB inhibition by p65 small hairpin RNA. Lapatinib but not other EGFR inhibitors synergized the anti-tumor activity of proteasome inhibitors both in vitro and in vivo. Our results suggest that treatment of TNBCs with lapatinib may enhance their oncogene addiction to NF-κB, and thus augment the anti-tumor activity of proteasome inhibitors. Conclusions These findings suggest that combination therapy of a proteasome inhibitor with lapatinib may benefit TNBC patients.
- Subjects :
- Receptor, ErbB-2
Estrogen receptor
Antineoplastic Agents
Triple Negative Breast Neoplasms
Mice, SCID
Lapatinib
Bortezomib
Erlotinib Hydrochloride
Gefitinib
Antineoplastic Combined Chemotherapy Protocols
medicine
Animals
Humans
Epidermal growth factor receptor
Phosphorylation
skin and connective tissue diseases
Triple-negative breast cancer
EGFR inhibitors
Medicine(all)
biology
business.industry
NF-kappa B
Boronic Acids
Xenograft Model Antitumor Assays
I-kappa B Kinase
ErbB Receptors
Pyrazines
Quinazolines
Proteasome inhibitor
Cancer research
biology.protein
Female
business
Proteasome Inhibitors
Research Article
medicine.drug
Subjects
Details
- ISSN :
- 1465542X
- Volume :
- 15
- Database :
- OpenAIRE
- Journal :
- Breast Cancer Research
- Accession number :
- edsair.doi.dedup.....036d1d40df152554b3d2101c033b53c3