HER2 Interconversion in CTCs

[PMID:27556950] [Nature]

HER2 expression identifies dynamic functional states within circulating breast cancer cells

“Here we analyse circulating tumour cells from 19 women with ER+/HER2primary tumours, 84% of whom had acquired circulating tumour cells expressing HER2.” “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 HER2phenotype.” “we have used primary and cultured CTCs from patients with ER+/HER2 breast cancer who developed metastatic multidrug-resistant disease to show that coexisting distinct HER2+ and HER2 tumour cell subpopulations may interconvert, with striking consequences for disease progression and drug response. The comparable tumour initiating potential and similar expression of stem cell marker ALDH1 in HER2+ and HER2 CTCs suggest underlying tumour cell plasticity in these advanced patient-derived breast CTC lines, rather than a hierarchical cancer stem-cell model as described in drug-resistant subpopulations within established breast cancer cell lines.” “we propose a dynamic model, in which the equilibrium between HER2+ and HER2 cells within a heterogeneous tumour population is driven by spontaneous interconversion between these phenotypes, with the more rapidly proliferating HER2+ cells prevalent under baseline conditions, and environmental or therapy-induced stress enhancing conversion to the more resistant HER2 phenotype.”

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