Format

Send to

Choose Destination
Nature. 2016 Sep 1;537(7618):102-106. doi: 10.1038/nature19328. Epub 2016 Aug 24.

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

Author information

1
Massachusetts General Hospital Cancer Center, Harvard Medical School, Charlestown, Massachusetts 02129, USA.
2
Department of Medicine, Harvard Medical School, Boston, Massachusetts 02114, USA.
3
Department of Surgery, Harvard Medical School, Boston, Massachusetts 02114, USA.
4
Department of Pathology, Harvard Medical School, Boston, Massachusetts 02114, USA.
5
Center for Bioengineering in Medicine and Shriners Hospital, Harvard Medical School, Boston, Massachusetts 02114, USA.
6
Howard Hughes Medical Institute, Chevy Chase, Maryland 20815, USA.

Abstract

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.

PMID:
27556950
PMCID:
PMC5161614
[Available on 2017-02-24]
DOI:
10.1038/nature19328
[Indexed for MEDLINE]
Free PMC Article

Conflict of interest statement

The authors declare no competing financial interests.

Supplemental Content

Full text links

Icon for Nature Publishing Group Icon for PubMed Central
Loading ...
Support Center