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.
Highlights
The cancer stem cell hypothesis proposes that cancers arise from and are maintained by a small population of cancer-initiating cells residing within tumor mass
In order to analyse the impact of Ataxia-Telangiectasia Mutated (ATM) kinase on formation of cells with a stem-like phenotype in breast cancer, we choose as cancer model system: 1) mammospheres derived from luminal estrogen receptor-positive HER2low breast cancer cell line (MCF7); 2) mammospheres derived from luminal estrogen receptor-positive HER2overexpressing breast cancer cell line (MCF7-human epidermal growth factor receptor 2 (HER2))
We previously demonstrated that ATM promotes HER2-dependent tumorigenesis in breast cancer, reporting a context-dependent role of ATM targeting in cancer [9]
Summary
The cancer stem cell hypothesis proposes that cancers arise from and are maintained by a small population of cancer-initiating cells residing within tumor mass. These cells are characterized by the re-expression of stem cell markers and self-renewal potential, and have been named cancer stem cells (CSCs) or more exactly cancer stem-like cells. The fate of cancer stem cells is determined by the “stem cell niche” in the tumor, which comprises stromal cells, cytokines, and growth factors. This niche is characterized by starvation and hypoxic conditions that are considered critical niche factors to promote invasive growth of tumors. Molecular mechanisms involved in their regulation, maintenance and resistance to therapies are peculiar and specific for this subpopulation of cells in the tumor and so targeting strategies for the destruction of CSCs specific signalling pathways provides a novel opportunity for cancer research [3]
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