HER2 expression identifies dynamic functional states within circulating breast cancer cells

DSpace/Manakin Repository

HER2 expression identifies dynamic functional states within circulating breast cancer cells

Citable link to this page

 

 
Title: HER2 expression identifies dynamic functional states within circulating breast cancer cells
Author: 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.

Note: Order does not necessarily reflect citation order of authors.

Citation: Jordan, 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.
Full Text & Related Files:
Abstract: Circulating 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.
Published Version: doi:10.1038/nature19328
Other Sources: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5161614/pdf/
Terms of Use: This article is made available under the terms and conditions applicable to Other Posted Material, as set forth at http://nrs.harvard.edu/urn-3:HUL.InstRepos:dash.current.terms-of-use#LAA
Citable link to this page: http://nrs.harvard.edu/urn-3:HUL.InstRepos:31731819
Downloads of this work:

Show full Dublin Core record

This item appears in the following Collection(s)

 
 

Search DASH


Advanced Search
 
 

Submitters