期刊
NATURE
卷 537, 期 7618, 页码 102-106出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/nature19328
关键词
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资金
- National Institutes of Health (NIH) [2RO1CA129933]
- Howard Hughes Medical Institute
- Breast Cancer Research Foundation
- National Foundation for Cancer Research
- Wellcome Trust [102696]
- NIH [2U01EB012493, T32 CA009361]
- Susan G. Komen Foundation [PDF16376429, K12 5K12CA087723]
Circulating tumour cells in women with advanced oestrogen receptor (ER)-positive/human epidermal growth factor receptor 2 (HER2)-negative breast cancer acquire a HER2-positive subpopulation after multiple courses of therapy(1,2). In contrast to HER2-amplified primary breast cancer, which is highly sensitive to HER2-targeted therapy, the clinical significance of acquired HER2 heterogeneity during the evolution of metastatic breast cancer is unknown. Here we analyse circulating tumour cells from 19 women with ER+/HER2(-) primary tumours, 84% of whom had acquired circulating tumour cells expressing HER2. Cultured circulating tumour cells maintain discrete HER2(+) and HER2(-) subpopulations: HER2+ circulating tumour cells are more proliferative but not addicted to HER2(-), consistent with activation of multiple signalling pathways; HER2(-) circulating tumour cells show activation of Notch and DNA damage pathways, exhibiting resistance to cytotoxic chemotherapy, but sensitivity to Notch inhibition. HER2(+) and HER2(-) circulating tumour cells interconvert spontaneously, with cells of one phenotype producing daughters of the opposite within four cell doublings. Although HER2(+) and HER2(-) circulating tumour cells have comparable tumour initiating potential, differential proliferation favours the HER2(+) state, while oxidative stress or cytotoxic chemotherapy enhances transition to the HER2(-) phenotype. Simultaneous treatment with paclitaxel and Notch inhibitors achieves sustained suppression of tumorigenesis in orthotopic circulating tumour cell-derived tumour models. Together, these results point to distinct yet interconverting phenotypes within patient-derived circulating tumour cells, contributing to progression of breast cancer and acquisition of drug resistance.
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