TY - JOUR
T1 - HER2 expression identifies dynamic functional states within circulating breast cancer cells
AU - Jordan, Nicole Vincent
AU - Bardia, Aditya
AU - Wittner, Ben S.
AU - Benes, Cyril
AU - Ligorio, Matteo
AU - Zheng, Yu
AU - Yu, Min
AU - Sundaresan, Tilak K.
AU - Licausi, Joseph A.
AU - Desai, Rushil
AU - O'Keefe, Ryan M.
AU - Ebright, Richard Y.
AU - Boukhali, Myriam
AU - Sil, Srinjoy
AU - Onozato, Maristela L.
AU - Iafrate, Anthony J.
AU - Kapur, Ravi
AU - Sgroi, Dennis
AU - Ting, David T.
AU - Toner, Mehmet
AU - Ramaswamy, Sridhar
AU - Haas, Wilhelm
AU - Maheswaran, Shyamala
AU - Haber, Daniel A.
N1 - Funding Information:
We thank the patients who participated in this study. This work was supported by National Institutes of Health (NIH) 2RO1CA129933, the Howard Hughes Medical Institute, the Breast Cancer Research Foundation, the National Foundation for Cancer Research (DAH) and Wellcome Trust 102696 (C.B.), NIH Quantum 2U01EB012493 (M.T., D.A.H.), T32 CA009361, Susan G. Komen Foundation PDF16376429 (N.V.J.), K12 5K12CA087723 (A.B.) and T32GM007753 (R.Y.E.). We thank D. Dombrowski (NIH 1S100D1016372-01) for expert flow cytometry.
PY - 2016/8/24
Y1 - 2016/8/24
N2 - 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.
AB - 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.
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U2 - 10.1038/nature19328
DO - 10.1038/nature19328
M3 - Article
C2 - 27556950
AN - SCOPUS:84984596113
SN - 0028-0836
VL - 537
SP - 102
EP - 106
JO - Nature
JF - Nature
IS - 7618
ER -