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Deciphering the gene expression network regulated by ETV7

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-Flouororuacil 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-b. 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-b 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-b, with the aim of avoiding resistance development and relapse in breast cancer.

ORGANISM(S): Homo sapiens

PROVIDER: GSE152580 | GEO | 2021/07/28

REPOSITORIES: GEO

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Project description:Lung Cancer (LC), colorectal cancer (CRC) and breast cancer (BC) are the major killers in oncology, accounting for about 40% of cancer deaths. Although progresses have been made in the last few years, unfortunately no patient with metastatic disease can obtain a definitive cure. A recent hypothesis is that cancer is driven by a small subpopulation of cells called "cancer stem cells" (CSCs) or "tumor initiating cells" with an unlimited proliferative potential and the ability to reproduce the original human tumor in experimental animal models. These cells are thought to be responsible for the development of the tumor and represent the only cell population able to sustain tumor growth and progression. Therefore, CSCs represent the elective target for new targeted therapies, endowed with high and selective toxicity towards the tumor but harmless towards normal cells. Current technologies allow us to isolate and expand in vitro the CSCs from tumor specimens, testing their sensitivity to different anticancer drugs in a short period of time. Therefore, there is the potential opportunity to identify LC, CRC and BC CSCs.This is a prospective study assessing feasibility of CSCS isolation in LC, CRC and BC. Patients with a previously performed diagnosis of LC, colon cancer or breast cancer with no further standard therapy options, with a Karnofsky performance status of 100% and with tumor tissue available will be considered eligible for the study. Tumor tissue will be collected before study entry, i.e tissue obtained during a diagnostic or therapeutical procedure, like surgery or biopsies with other purposes than the protocol. In vitro tumor sensitivity to chemotherapy drugs will be tested on tumor cell cultures per each patient. Drugs and their combination will be considered effective and if they kill ≥ 60% of tumor stem cells in vitro test. By using cancer spheres the investigators will also generate orthotopic xenograft models that recapitulate the parental tumor behaviour, including the aggressive features and the invasiveness potential. Orthotopic injection technique will be assessed in 5 weeks-old NOD/SCID mice

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Deciphering the gene expression network regulated by ETV7

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