Higher levels of p62, keratins, and ER chaperones were also observed in autophagy-deficient mammary tissues and beclin 1 +/− immortalized mouse mammary epithelial cell (iMMEC)–generated tumors. Furthermore, autophagy defects deregulated keratin homeostasis in mammary cells, and phospho(Ser73)-K8, which is involved in stress-induced keratin remodeling, accumulated in metabolically stressed iMMECs in a p62-dependent manner upon autophagy inhibition. Defective autophagy was also associated with accumulation of p62, a scaffolding protein involved in cell signaling, receptor internalization, and protein turnover ( 11) during metabolic stress and recovery. We found that ER chaperones, oxidative stress–mitigating mitochondrial proteins, enzymes involved in glucose metabolism, and cytoskeletal proteins were upregulated in mammary cells under stress, preferentially in beclin 1 +/− iMMECs. ©2010 AACR.īecause autophagy mediates protein degradation, we used a proteomic approach to investigate how beclin 1 +/+ and beclin 1 +/− iMMECs respond to metabolic stress. High phospho(Ser73)-K8 expression may be a marker of autophagy functional status in breast tumors and, as such, could have therapeutic implications for breast cancer patients. Furthermore, autophagy regulates keratin homeostasis in the mammary gland via a p62-dependent mechanism. Thus, autophagy preserves cellular fitness by limiting ER and oxidative stress, a function potentially important in autophagy-mediated suppression of mammary tumorigenesis. In human breast tumors, high phospho(Ser73)-K8 levels are inversely correlated with Beclin 1 expression. We now report that autophagy deficiency is associated with endoplasmic reticulum (ER) and oxidative stress, and with deregulation of p62-mediated keratin homeostasis in mammary cells, allograft tumors, and mammary tissues from genetically engineered mice. We previously showed that autophagy-defective immortalized mouse mammary epithelial cells are susceptible to metabolic stress, DNA damage, and genomic instability. Defective autophagy is implicated in human pathology, as disruption of protein and organelle homeostasis enables disease-promoting mechanisms such as toxic protein aggregation, oxidative stress, genomic damage, and inflammation. Autophagy is activated in response to cellular stressors and mediates lysosomal degradation and recycling of cytoplasmic material and organelles as a temporary cell survival mechanism.
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