HER2 expression identifies dynamic functional states within circulating breast cancer cells
Jordan, Nicole Vincent
Sundaresan, Tilak K.
Licausi, Joseph A.
O’Keefe, Ryan M.
MetadataShow full item record
CitationJordan, 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.
AbstractCirculating 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.
Citable link to this pagehttp://nrs.harvard.edu/urn-3:HUL.InstRepos:31731819