Using the MCF10A/MCF10CA1a Breast Cancer Progression Cell Line Model to Investigate the Effect of Active, Mutant Forms of EGFR in Breast Cancer Development and Treatment Using Gefitinib
| Autor: | Michael C.J. Quinn, Adrian P. Wiegmans, Jodi M. Saunus, Nic Waddell, Tatjana Seidens, Sean M. Grimmond, Darrell C. Bessette, Sunil R. Lakhani, Fares Al-Ejeh, Amy McCart-Reed, Georgia Chenevix-Trench, Wei Shi, Kum Kum Khanna, Sibylle Cocciardi, Peter T. Simpson, Erik Tilch |
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| Jazyk: | angličtina |
| Rok vydání: | 2015 |
| Předmět: |
medicine.medical_treatment
Gene Expression lcsh:Medicine medicine.disease_cause Targeted therapy Metastasis Mice Phosphatidylinositol 3-Kinases 0302 clinical medicine Cell Movement Exome Epidermal growth factor receptor skin and connective tissue diseases lcsh:Science Triple-negative breast cancer 0303 health sciences Multidisciplinary biology Gefitinib 3. Good health ErbB Receptors Cell Transformation Neoplastic 030220 oncology & carcinogenesis Female Research Article Plasmids medicine.drug DNA Copy Number Variations Class I Phosphatidylinositol 3-Kinases Mice Nude Antineoplastic Agents Breast Neoplasms Transfection Models Biological Cell Line 03 medical and health sciences Breast cancer Growth factor receptor Cell Line Tumor medicine Animals Humans Protein Kinase Inhibitors Cell Proliferation 030304 developmental biology lcsh:R medicine.disease Xenograft Model Antitumor Assays Drug Resistance Neoplasm Mutation Quinazolines Cancer research biology.protein lcsh:Q Carcinogenesis |
| Zdroj: | PLoS ONE, Vol 10, Iss 5, p e0125232 (2015) PLoS ONE |
| ISSN: | 1932-6203 |
| Popis: | Background Basal-like and triple negative breast cancer (TNBC) share common molecular features, poor prognosis and a propensity for metastasis to the brain. Amplification of epidermal growth factor receptor (EGFR) occurs in ~50% of basal-like breast cancer, and mutations in the epidermal growth factor receptor (EGFR) have been reported in up to ~ 10% of Asian TNBC patients. In non-small cell lung cancer several different mutations in the EGFR tyrosine kinase domain confer sensitivity to receptor tyrosine kinase inhibitors, but the tumourigenic potential of EGFR mutations in breast cells and their potential for targeted therapy is unknown. Materials and Methods Constructs containing wild type, G719S or E746-A750 deletion mutant forms of EGFR were transfected into the MCF10A breast cells and their tumorigenic derivative, MCF10CA1a. The effects of EGFR over-expression and mutation on proliferation, migration, invasion, response to gefitinib, and tumour formation in vivo was investigated. Copy number analysis and whole exome sequencing of the MCF10A and MCF10CA1a cell lines were also performed. Results Mutant EGFR increased MCF10A and MCF10CA1a proliferation and MCF10A gefitinib sensitivity. The EGFR-E746-A750 deletion increased MCF10CA1a cell migration and invasion, and greatly increased MCF10CA1a xenograft tumour formation and growth. Compared to MCF10A cells, MCF10CA1a cells exhibited large regions of gain on chromosomes 3 and 9, deletion on chromosome 7, and mutations in many genes implicated in cancer. Conclusions Mutant EGFR enhances the oncogenic properties of MCF10A cell line, and increases sensitivity to gefitinib. Although the addition of EGFR E746-A750 renders the MCF10CA1a cells more tumourigenic in vivo it is not accompanied by increased gefitinib sensitivity, perhaps due to additional mutations, including the PIK3CA H1047R mutation, that the MCF10CA1a cell line has acquired. Screening TNBC/basal-like breast cancer for EGFR mutations may prove useful for directing therapy but, as in non-small cell lung cancer, accompanying mutations in PIK3CA may confer gefitinib resistance. |
| Databáze: | OpenAIRE |
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