Autophagy mitigates metabolic stress and genome damage in mammary tumorigenesis.

By V. Karantza-Wadsworth, S. Patel, Olga Kravchuk, Guanghua Chen, Robin Mathew, Shengkan Jin, E. White. Genes & Development, 2007

882 citations recorded by the source corpus.

Autophagy is a catabolic process involving self-digestion of cellular organelles during starvation as a means of cell survival; however, if it proceeds to completion, autophagy can lead to cell death. Autophagy is also a haploinsufficient tumor suppressor mechanism for mammary tumorigenesis, as the essential autophagy regulator beclin1 is monoallelically deleted in breast carcinomas. However, the mechanism by which autophagy suppresses breast cancer remains elusive. Here we show that allelic loss of beclin1 and defective autophagy sensitized mammary epithelial cells to metabolic stress and accelerated lumen formation in mammary acini. Autophagy defects also activated the DNA damage response in vitro and in mammary tumors in vivo, promoted gene amplification, and synergized with defective apoptosis to promote mammary tumorigenesis. Therefore, we propose that autophagy limits metabolic stress to protect the genome, and that defective autophagy increases DNA damage and genomic instability that ultimately facilitate breast cancer progression.

Subfields: Epidemiology, Molecular Biology

View Paper: https://www.semanticscholar.org/paper/d4d21a533a2225c18bf8a9051a55ae1615171948

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Citations in the corpus

Autophagy-deficient mice develop multiple liver tumors. (2011, result): “These data are consistent with the recent in vitro and in vivo studies (Karantza-Wadsworth et al. 2007; Mathew et al. 2007).”
The unfolded protein response protects human tumor cells during hypoxia through regulation of the autophagy genes MAP1LC3B and ATG5. (2010, background): “During carcinogenesis autophagy suppresses tumor progression through stabilization of the genome (58, 59), perhaps related to the inability to clear the cell of damaged organelles or toxic protein aggregates.”
Cytosolic FoxO1 is essential for the induction of autophagy and tumour suppressor activity (2010, background): “Accumulated evidence has shown that the autophagic process is related to cell cycle regulation, starvation adaptation, ageing, and cancer developmen”
Beclin1 Controls the Levels of p53 by Regulating the Deubiquitination Activity of USP10 and USP13 (2011, neutral): “The ability of Beclin1 to regulate the levels of p53 provides a mechanism underlying the observations that monoallelic loss of beclin1 is sufficient to lead to DNA damage and genomic instability via gene amplification (Karantza-Wadsworth et al., 2007).”
Autophagy in the pathogenesis of disease. (2008, neutral): “Further, immortalized kidney and mammary epithelial cells derived from beclin 1 heterozygous-deficient mice are more tumorigenic than those derived from wildtype mice (Karantza-Wadsworth et al., 2007; Mathew et al., 2007b).”
Autophagy and autophagy-related proteins in cancer (2020, background): “The spontaneous frequency of malignancies is higher in the Beclin1 mouse model [192, 193], indicating that autophagy is a tumorsuppression mechanism [11, 25, 190, 194].”
Oxidative stress and autophagy: the clash between damage and metabolic needs (2014, background): “This assumption provides a general explanation of the important role of autophagy in maintaining genomic stability that is strictly related to its tumour suppressor function.(106,113,114) However, evidence supporting a direct role for autophagy in the DDR, at least in mammals, is still lacking.”
The Double-edged Sword of Autophagy Modulation in Cancer (2009, background): “but it is not known if this contributes to inflammation and increased tumorigenesis (15).”
Autophagy as a target for anticancer therapy (2011, background): “In preclinical experiments, autophagy-deficient mammary cells exhibited increased DNA instability, ultimately facilitating mammary tumorigenesis”
Autophagy: process and function. (2007, background): “Furthermore, DNA damage and genomic instability were demonstrated in mammary epithelial cells in response to metabolic stress when both autophagy and apoptosis were suppressed (Karantza-Wadsworth et al. 2007).”
The dynamic nature of autophagy in cancer. (2011, background): “Further studies from the White laboratory (Degenhardt et al. 2006; Karantza-Wadsworth et al. 2007; Mathew et al. 2007) have shown that loss of autophagy leads to genomic instability and aneuploidy, which promotes tumorigenesis.”