Oncotarget

Research Papers:

Breast cancer stem cell-like cells generated during TGFβ-induced EMT are radioresistant

Julie Konge, François Leteurtre, Maud Goislard, Denis Biard, Sandrine Morel-Altmeyer, Aurélie Vaurijoux, Gaetan Gruel, Sylvie Chevillard and Jérôme Lebeau _

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Oncotarget. 2018; 9:23519-23531. https://doi.org/10.18632/oncotarget.25240

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Abstract

Julie Konge1, François Leteurtre1, Maud Goislard1, Denis Biard2, Sandrine Morel-Altmeyer1, Aurélie Vaurijoux3, Gaetan Gruel3, Sylvie Chevillard1,* and Jérôme Lebeau1,*

1CEA, Institut de Biologie François Jacob, DSV, iRCM, SREIT, Laboratoire de Cancérologie Expérimentale (LCE), Université Paris-Saclay, F-92265 Fontenay-aux-Roses, France

2CEA, Institut de Biologie François Jacob, SEPIA, Team Cellular Engineering and Human Syndromes, Université Paris-Saclay, F-92265 Fontenay-aux-Roses, France

3Institut de Radioprotection et de Sureté Nucléaire (IRSN), Laboratoire de Dosimétrie Biologique, 92262 Fontenay-aux-Roses Cedex, France

*These authors contributed equally to this work

Correspondence to:

Jérôme Lebeau, email: jerome.lebeau@cea.fr

Keywords: epithelial-mesenchymal transition; breast cancer; radioresistance; cancer stem cells

Received: August 24, 2017     Accepted: April 04, 2018     Published: May 04, 2018

ABSTRACT

Failure of conventional antitumor therapy is commonly associated with cancer stem cells (CSCs), which are often defined as inherently resistant to radiation and chemotherapeutic agents. However, controversy about the mechanisms involved in the radiation response remains and the inherent intrinsic radioresistance of CSCs has also been questioned. These discrepancies observed in the literature are strongly associated with the cell models used. In order to clarify these contradictory observations, we studied the radiosensitivity of breast CSCs using purified CD24−/low/CD44+ CSCs and their corresponding CD24+/CD44low non-stem cells. These cells were generated after induction of the epithelial-mesenchymal transition (EMT) by transforming growth factor β (TGFβ) in immortalized human mammary epithelial cells (HMLE). Consequently, these 2 cellular subpopulations have an identical genetic background, their differences being related exclusively to TGFβ-induced cell reprogramming. We showed that mesenchymal CD24−/low/CD44+ CSCs are more resistant to radiation compared with CD24+/CD44low parental cells. Cell cycle distribution and free radical scavengers, but not DNA repair efficiency, appeared to be intrinsic determinants of cellular radiosensitivity. Finally, for the first time, we showed that reduced radiation-induced activation of the death receptor pathways (FasL, TRAIL and TNF-α) at the transcriptional level was a key causal event in the radioresistance of CD24−/low/CD44+ cells acquired during EMT.


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