Abstract
Cancer stem cells (CSCs) represent a population of cells within the tumor able to drive tumorigenesis and known to be highly resistant to conventional chemotherapy and radiotherapy. In this work, we show a new role for ETV7, a transcriptional repressor member of the ETS family, in promoting breast cancer stem-like cells plasticity and resistance to chemo- and radiotherapy in breast cancer (BC) cells. We observed that MCF7 and T47D BC-derived cells stably over-expressing ETV7 showed reduced sensitivity to the chemotherapeutic drug 5-fluorouracil and to radiotherapy, accompanied by an adaptive proliferative behavior observed in different culture conditions. We further noticed that alteration of ETV7 expression could significantly affect the population of breast CSCs, measured by CD44+/CD24low cell population and mammosphere formation efficiency. By transcriptome profiling, we identified a signature of Interferon-responsive genes significantly repressed in cells over-expressing ETV7, which could be responsible for the increase in the breast CSCs population, as this could be partially reverted by the treatment with IFN-β. Lastly, we show that the expression of the IFN-responsive genes repressed by ETV7 could have prognostic value in breast cancer, as low expression of these genes was associated with a worse prognosis. Therefore, we propose a novel role for ETV7 in breast cancer stem cells’ plasticity and associated resistance to conventional chemotherapy and radiotherapy, which involves the repression of a group of IFN-responsive genes, potentially reversible upon IFN-β treatment. We, therefore, suggest that an in-depth investigation of this mechanism could lead to novel breast CSCs targeted therapies and to the improvement of combinatorial regimens, possibly involving the therapeutic use of IFN-β, with the aim of avoiding resistance development and relapse in breast cancer.
Highlights
Breast cancer is the most frequent tumor and the leading cause of cancer-related deaths in women [1]
In the light of these results, we propose a novel role for ETV7 as a regulator of breast cancer stem cell-like plasticity, which is mediated by the repression of IFN-stimulated genes and that can be partially reverted by the stimulation of IFN response with IFN-β
We have recently published a novel mechanism of ETV7-mediated resistance to the chemotherapeutic agent Doxorubicin which involves the downregulation of DNAJC15 tumor suppressor leading to an increased expression of ABCB1 efflux pump [36]
Summary
Breast cancer is the most frequent tumor and the leading cause of cancer-related deaths in women [1]. Breast cancer is a highly genetically heterogeneous disease [2], and current therapeutic approaches are chosen based on the subtype of cancer, stage, mass and localization of the tumors among several parameters [3]. The most common therapeutic strategies rely both on local (e.g., surgery and radiotherapy) and systemic treatments (e.g., chemotherapy, endocrine/hormonal, and targeted therapy) [4]. Hormone-dependent breast cancers, such as luminal breast cancers, frequently become refractory to the initially effective hormonal treatments, eventually requiring chemotherapy [5]. Chemotherapy, still represents the most common option for advanced breast cancers. Cancer cells can develop drug resistance, resulting in treatment failure and recurrence [7, 8]
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