Abstract
Gene expression analysis of The Cancer Genome Atlas (TCGA) breast cancer data set show that miR-20a is upregulated in human breast cancer, especially in triple-negative subtype. Gene Set Enrichment Analysis suggests that miR-20a expression negatively correlates with the autophagy/lysosome pathway. We report here that miR-20a inhibits the basal and nutrient starvation-induced autophagic flux and lysosomal proteolytic activity, increases intracellular reactive oxygen species levels and DNA damage response by targeting several key regulators of autophagy, including BECN1, ATG16L1 and SQSTM1. Re-introduction of exogenous BECN1, ATG16L1 or SQSTM1 reverses the inhibitory effect of miR-20a on autophagy and decreases DNA damage. A negative correlation between miR-20a and its target genes is observed in breast cancer tissues. Lower levels of BECN1, ATG16L1 and SQSTM1 are more common in triple-negative cancers than in other subtypes. High levels of miR-20a also associate with higher frequency of copy-number alterations and DNA mutations in breast cancer patients. Further studies in a xenograft mouse model show that miR-20a promotes tumor initiation and tumor growth. Collectively, these findings suggest that miR-20a-mediated autophagy defect might be a new mechanism underlying the oncogenic function of miRNA during breast tumorigenesis.
Highlights
Autophagy plays important function in regulating cell homeostasis
We identified miR-20a expression signature predictive of estrogen receptor (ER), progesterone receptor (PR) or human epidermal growth factor receptor 2 (HER2)
These results demonstrate that miR-20a might be a potential diagnostic marker to distinguish triple-negative breast cancer from other subtypes
Summary
Autophagy plays important function in regulating cell homeostasis. Autophagy performs homeostatic ‘quality control’ functions to eliminate unfolded proteins or damaged organelles. Dysfunction in autophagy pathway suppresses tumor proliferation, dissemination and metastasis.[15] Inhibition of autophagy increases sensitivity of tumor cells to chemotherapeutic agents as well as radiation therapy.[16,17,18] Deletion of FIP200, a component of the ULK1– ATG13–FIP200 complex that is required for autophagosome formation, suppresses tumor initiation and progression. These findings strongly support the role of autophagy in oncogenesis in vivo.[19]
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