HER2 expression identifies dynamic functional states within circulating breast cancer cells

作者：Jordan, Nicole Vincent^*; Bardia, Aditya; Wittner, Ben S.; Benes, Cyril; Ligorio, Matteo; Zheng, Yu; Yu, Min; Sundaresan, Tilak K.; Licausi, Joseph A.; Desai, Rushil; O'Keefe, Ryan M.; Ebright, Richard Y.; Boukhali, Myriam; Sil, Srinjoy; Onozato, Maristela L.; Iafrate, Anthony J.; Kapur, Ravi; Sgroi, Dennis; Ting, David T.; Toner, Mehmet; Ramaswamy, Sridhar; Haas, Wilhelm; Maheswaran, Shyamala; Haber, Daniel A.

来源：Nature, 2016, 537(7618): 102-106.

DOI：10.1038/nature19328

• TUMOR-CELLS
• STEM-CELLS
• SIGNALING PATHWAYS
• HEDGEHOG PATHWAY
• NOTCH
• INHIBITOR
• TUMORIGENESIS
• TRASTUZUMAB
• RECURRENCE
• AXIS

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.

• 出版日期2016-9-1