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

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.

journal_name

Nature

journal_title

Nature

authors

Jordan NV,Bardia A,Wittner BS,Benes C,Ligorio M,Zheng Y,Yu M,Sundaresan TK,Licausi JA,Desai R,O'Keefe RM,Ebright RY,Boukhali M,Sil S,Onozato ML,Iafrate AJ,Kapur R,Sgroi D,Ting DT,Toner M,Ramaswamy S,Haas W,Mah

doi

10.1038/nature19328

subject

Has Abstract

pub_date

2016-09-01 00:00:00

pages

102-106

issue

7618

eissn

0028-0836

issn

1476-4687

pii

nature19328

journal_volume

537

pub_type

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