Abstract
BackgroundBasal-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 MethodsConstructs 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.ResultsMutant 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.ConclusionsMutant 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.
Highlights
Breast cancer is the most common cancer in women and the second most common cause of cancer death, after lung cancer, in women in Australia
Mutant epidermal growth factor receptor (EGFR) enhances the oncogenic properties of MCF10A cell line, and increases sensitivity to gefitinib
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
Summary
Breast cancer is the most common cancer in women and the second most common cause of cancer death, after lung cancer, in women in Australia (http://www.aihw.gov.au/). The most aggressive forms of breast cancer are triple negative breast cancer (TNBC), defined histologically by the absence of estrogen receptor (ER), progesterone receptor (PR) and epidermal growth factor 2 (HER2), and a subset of TNBC referred to as basal-like breast cancer, characterized by CK5/6 and/or epidermal growth factor receptor (EGFR) expression [1,2,3] Both tumour types are associated with shorter disease-free and overall survival, propensity for lung and brain metastases, younger age at diagnosis, African-American descent and lack of response to endocrine or HER2-mediated therapies [4,5,6,7,8,9,10,11,12]. 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
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