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The Cancer Stem Cells (CSCs) hypothesis implies the existence of progenitor breast cancer cells with de-novo resistance toward anti oestrogen-receptor therapies. Here we demonstrate that putative CSCs are epigenetically distinct from the main tumour population. CSCs are resilient but not completely resistant requiring an additional layer of epigenetic reprogramming to evolve into a fully drug-resistant population. Potential CSCs subpopulations can be identified in primary ER patients but are promptly selected by short-term treatment and further expand in metastatic disease after chronic treatment. Using a single cell assay, we demonstrate that acute endocrine treatment has a differential impact on asymmetric division and cell cycle dynamics in CSCs and non-CSCs. Finally, we identify Notch signalling as the main CSCs gatekeeper of cell plasticity. Using anti-Notch therapy, we can force CSCs differentiation into a targetable subpopulation. Our data suggest that epigenetic plasticity contributes to drug resistance and might represent a novel therapeutic target. |