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HER2 expression identifies dynamic functional states within circulating breast cancer cells
Open accessAbstract
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. 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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Metadata
- Authors
- Jordan, N. V., Bardia, A., Wittner, B. S., Benes, C., Ligorio, M., Zheng, Y., Yu, M., Sundaresan, T. K., Licausi, J. A., Desai, R., O’Keefe, R. M., Ebright, R. Y., Boukhali, M., Sil, S., Onozato, M. L., Iafrate, A. J., Kapur, R., Sgroi, D., Ting, D. T., Toner, M., Ramaswamy, S., Haas, W., Maheswaran, S., & Haber, D. A.
- Venue
- Nature
- Published
- 2016-08-24
- Volume
- 537
- Issue
- 7618
- Pages
- 102-106
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- OpenAlex
- W2512004978
- Cited by
- 406
- References
- 34
- FWCI
- 22.87
- Type
- journal article
- Language
- en
- Open access
- green
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- Jordan, N. V., Bardia, A., Wittner, B. S., Benes, C., Ligorio, M., Zheng, Y., Yu, M., Sundaresan, T. K., Licausi, J. A., Desai, R., O’Keefe, R. M., Ebright, R. Y., Boukhali, M., Sil, S., Onozato, M. L., Iafrate, A. J., Kapur, R., Sgroi, D., Ting, D. T., . . . Haber, D. A. (2016). HER2 expression identifies dynamic functional states within circulating breast cancer cells. Nature. https://doi.org/10.1038/nature19328
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