Effect of Lapatinib on the Outgrowth of Metastatic Breast Cancer Cells to the Brain
| Autor: | Julie L. Bronder, Brunilde Gril, David J. Liewehr, Maria Merino, Diane Palmieri, Stephen D. Rubin, Patricia S. Steeg, Eleazar Vega-Valle, Jeanne M. Herring, Seth M. Steinberg, Lionel Feigenbaum |
|---|---|
| Rok vydání: | 2008 |
| Předmět: |
Cancer Research
Pathology Receptor ErbB-2 Mice Cell Movement Trastuzumab Epidermal growth factor receptor Phosphorylation RNA Small Interfering skin and connective tissue diseases Mice Inbred BALB C biology Brain Neoplasms Immunochemistry Articles Metastatic breast cancer ErbB Receptors Gene Expression Regulation Neoplastic Oncology Research Design Female Breast disease Signal Transduction medicine.drug medicine.medical_specialty Immunoblotting Antineoplastic Agents Breast Neoplasms Transfection Lapatinib Breast cancer Cell Line Tumor Biomarkers Tumor medicine Animals Humans Gene Silencing Protein Kinase Inhibitors Cell Proliferation Analysis of Variance business.industry Cancer medicine.disease Xenograft Model Antitumor Assays Disease Models Animal Quinazolines Cancer research biology.protein business Brain metastasis |
| Zdroj: | JNCI Journal of the National Cancer Institute. 100:1092-1103 |
| ISSN: | 1460-2105 0027-8874 |
| Popis: | The brain is increasingly being recognized as a sanctuary site for metastatic tumor cells in women with HER2-overexpressing breast cancer who receive trastuzumab therapy. There are no approved or widely accepted treatments for brain metastases other than steroids, cranial radiotherapy, and surgical resection. We examined the efficacy of lapatinib, an inhibitor of the epidermal growth factor receptor (EGFR) and HER2 kinases, for preventing the outgrowth of breast cancer cells in the brain in a mouse xenograft model of brain metastasis.EGFR-overexpressing MDA-MB-231-BR (231-BR) brain-seeking breast cancer cells were transfected with an expression vector that contained or lacked the HER2 cDNA and used to examine the effect of lapatinib on the activation (ie, phosphorylation) of cell signaling proteins by immunoblotting, on cell growth by the tetrazolium salt 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide assay, and on cell migration using a Boyden chamber assay. The outgrowth of large (ie,50 microm(2)) and micrometastases was counted in brain sections from nude mice that had been injected into the left cardiac ventricle with 231-BR cells and, beginning 5 days later, treated by oral gavage with lapatinib or vehicle (n = 22-26 mice per treatment group). All statistical tests were two-sided.In vitro, lapatinib inhibited the phosphorylation of EGFR, HER2, and downstream signaling proteins; cell proliferation; and migration in 231-BR cells (both with and without HER2). Among mice injected with 231-BR-vector cells, those treated with 100 mg lapatinib/kg body weight had 54% fewer large metastases 24 days after starting treatment than those treated with vehicle (mean number of large metastases per brain section: 1.56 vs 3.36, difference = 1.80, 95% confidence interval [CI] = 0.92 to 2.68, P.001), whereas treatment with 30 mg lapatinib/kg body weight had no effect. Among mice injected with 231-BR-HER2 cells, those treated with either dose of lapatinib had 50%-53% fewer large metastases than those treated with vehicle (mean number of large metastases per brain section, 30 mg/kg vs vehicle: 3.21 vs 6.83, difference = 3.62, 95% CI = 2.30 to 4.94, P.001; 100 mg/kg vs vehicle: 3.44 vs 6.83, difference = 3.39, 95% CI = 2.08 to 4.70, P.001). Immunohistochemical analysis revealed reduced phosphorylation of HER2 in 231-BR-HER2 cell-derived brain metastases from mice treated with the higher dose of lapatinib compared with 231-BR-HER2 cell-derived brain metastases from vehicle-treated mice (P.001).Lapatinib is the first HER2-directed drug to be validated in a preclinical model for activity against brain metastases of breast cancer. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|