Abstract
The efficacy of Ataxia-Telangiectasia Mutated (ATM) kinase signalling inhibition in cancer therapy is tempered by the identification of new emerging functions of ATM, which suggests that the role of this protein in cancer progression is complex. We recently demonstrated that this tumor suppressor gene could act as tumor promoting factor in HER2 (Human Epidermal Growth Factor Receptor 2) positive breast cancer. Herein we put in evidence that ATM expression sustains the proportion of cells with a stem-like phenotype, measured as the capability to form mammospheres, independently of HER2 expression levels. Transcriptomic analyses revealed that, in mammospheres, ATM modulates the expression of cell cycle-, DNA repair- and autophagy-related genes. Among these, the silencing of the autophagic gene, autophagy related 4C cysteine peptidase (ATG4C), impairs mammosphere formation similarly to ATM depletion. Conversely, ATG4C ectopic expression in cells silenced for ATM expression, rescues mammospheres growth. Finally, tumor array analyses, performed using public data, identify a significant correlation between ATM and ATG4C expression levels in all human breast cancer subtypes, except for the basal-like one. Overall, we uncover a new connection between ATM kinase and autophagy regulation in breast cancer. We demonstrate that, in breast cancer cells, ATM and ATG4C are essential drivers of mammosphere formation, suggesting that their targeting may improve current approaches to eradicate breast cancer cells with a stem-like phenotype.
| Original language | English |
|---|---|
| Pages (from-to) | 21692-21709 |
| Number of pages | 18 |
| Journal | Oncotarget |
| Volume | 8 |
| Issue number | 13 |
| DOIs | |
| Publication status | Published - Jan 1 2017 |
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Keywords
- ATG4
- ATM kinase
- Autophagy
- Breast cancer stem cells (BCSCs)
- Mammospheres
ASJC Scopus subject areas
- Oncology
Cite this
ATM kinase sustains breast cancer stem-like cells by promoting ATG4C expression and autophagy. / Antonelli, Martina; Strappazzon, Flavie; Arisi, Ivan; Brandi, Rossella; D'Onofrio, Mara; Sambucci, Manolo; Manic, Gwenola; Vitale, Ilio; Barilà, Daniela; Stagni, Venturina.
In: Oncotarget, Vol. 8, No. 13, 01.01.2017, p. 21692-21709.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - ATM kinase sustains breast cancer stem-like cells by promoting ATG4C expression and autophagy
AU - Antonelli, Martina
AU - Strappazzon, Flavie
AU - Arisi, Ivan
AU - Brandi, Rossella
AU - D'Onofrio, Mara
AU - Sambucci, Manolo
AU - Manic, Gwenola
AU - Vitale, Ilio
AU - Barilà, Daniela
AU - Stagni, Venturina
PY - 2017/1/1
Y1 - 2017/1/1
N2 - The efficacy of Ataxia-Telangiectasia Mutated (ATM) kinase signalling inhibition in cancer therapy is tempered by the identification of new emerging functions of ATM, which suggests that the role of this protein in cancer progression is complex. We recently demonstrated that this tumor suppressor gene could act as tumor promoting factor in HER2 (Human Epidermal Growth Factor Receptor 2) positive breast cancer. Herein we put in evidence that ATM expression sustains the proportion of cells with a stem-like phenotype, measured as the capability to form mammospheres, independently of HER2 expression levels. Transcriptomic analyses revealed that, in mammospheres, ATM modulates the expression of cell cycle-, DNA repair- and autophagy-related genes. Among these, the silencing of the autophagic gene, autophagy related 4C cysteine peptidase (ATG4C), impairs mammosphere formation similarly to ATM depletion. Conversely, ATG4C ectopic expression in cells silenced for ATM expression, rescues mammospheres growth. Finally, tumor array analyses, performed using public data, identify a significant correlation between ATM and ATG4C expression levels in all human breast cancer subtypes, except for the basal-like one. Overall, we uncover a new connection between ATM kinase and autophagy regulation in breast cancer. We demonstrate that, in breast cancer cells, ATM and ATG4C are essential drivers of mammosphere formation, suggesting that their targeting may improve current approaches to eradicate breast cancer cells with a stem-like phenotype.
AB - The efficacy of Ataxia-Telangiectasia Mutated (ATM) kinase signalling inhibition in cancer therapy is tempered by the identification of new emerging functions of ATM, which suggests that the role of this protein in cancer progression is complex. We recently demonstrated that this tumor suppressor gene could act as tumor promoting factor in HER2 (Human Epidermal Growth Factor Receptor 2) positive breast cancer. Herein we put in evidence that ATM expression sustains the proportion of cells with a stem-like phenotype, measured as the capability to form mammospheres, independently of HER2 expression levels. Transcriptomic analyses revealed that, in mammospheres, ATM modulates the expression of cell cycle-, DNA repair- and autophagy-related genes. Among these, the silencing of the autophagic gene, autophagy related 4C cysteine peptidase (ATG4C), impairs mammosphere formation similarly to ATM depletion. Conversely, ATG4C ectopic expression in cells silenced for ATM expression, rescues mammospheres growth. Finally, tumor array analyses, performed using public data, identify a significant correlation between ATM and ATG4C expression levels in all human breast cancer subtypes, except for the basal-like one. Overall, we uncover a new connection between ATM kinase and autophagy regulation in breast cancer. We demonstrate that, in breast cancer cells, ATM and ATG4C are essential drivers of mammosphere formation, suggesting that their targeting may improve current approaches to eradicate breast cancer cells with a stem-like phenotype.
KW - ATG4
KW - ATM kinase
KW - Autophagy
KW - Breast cancer stem cells (BCSCs)
KW - Mammospheres
UR - http://www.scopus.com/inward/record.url?scp=85016411430&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85016411430&partnerID=8YFLogxK
U2 - 10.18632/oncotarget.15537
DO - 10.18632/oncotarget.15537
M3 - Article
VL - 8
SP - 21692
EP - 21709
JO - Oncotarget
JF - Oncotarget
SN - 1949-2553
IS - 13
ER -