Jordan, Nicole VincentBardia, AdityaWittner, BenBenes, CyrilLigorio, MatteoZheng, YuYu, MinSundaresan, Tilak K.Licausi, Joseph A.Desai, RushilO’Keefe, Ryan M.Ebright, RichardBoukhali, MyriamSil, SrinjoyOnozato, Maristela LikaIafrate, AnthonyKapur, RaviSgroi, DennisTing, DavidToner, MehmetRamaswamy, SridharHaas, WilhelmMaheswaran, ShyamalaHaber, Daniel2017-03-282016Jordan, N. V., A. Bardia, B. S. Wittner, C. Benes, M. Ligorio, Y. Zheng, M. Yu, et al. 2016. “HER2 expression identifies dynamic functional states within circulating breast cancer cells.” Nature 537 (7618): 102-106. doi:10.1038/nature19328. http://dx.doi.org/10.1038/nature19328.http://nrs.harvard.edu/urn-3:HUL.InstRepos:31731819Circulating tumor cells (CTCs) in women with advanced estrogen receptor-positive/HER2-negative breast cancer acquire a HER2-positive subpopulation following multiple courses of therapy1,2. 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 analyzed CTCs from 19 ER+/HER2− patients, 84% of whom had acquired CTCs expressing HER2. Cultured CTCs maintain discrete HER2+ and HER2− subpopulations: HER2+ CTCs are more proliferative but not addicted to HER2, consistent with activation of multiple signaling pathways. HER2− CTCs show activation of Notch and DNA damage pathways, exhibiting resistance to cytotoxic chemotherapy, but sensitivity to Notch inhibition. HER2+ and HER2− CTCs interconvert spontaneously, with cells of one phenotype producing daughters of the opposite within four cell doublings. While HER2+ and HER2− CTCs have comparable tumor initiating potential, differential proliferation favors 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 CTC-derived tumor models. Together, these results point to distinct yet interconverting phenotypes within patient-derived CTCs, contributing to progression of breast cancer and acquisition of drug resistance.en-USJournal Article2017-03-2810.1038/nature19328