Autophagy Regulates Keratin 8 Homeostasis in Mammary Epithelial Cells and in Breast Tumors

Abstract

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. 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. We previously showed that autophagy-defective immortalized mouse mammary epithelial cells are susceptible to metabolic stress, DNA damage, and genomic instability. 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. In human breast tumors, high phospho(Ser73)-K8 levels are inversely correlated with Beclin 1 expression. Thus, autophagy preserves cellular fitness by limiting ER and oxidative stress, a function potentially important in autophagy-mediated suppression of mammary tumorigenesis. Furthermore, autophagy regulates keratin homeostasis in the mammary gland via a p62-dependent mechanism. 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. Mol Cancer Res; 8(6); 873-84. ©2010 AACR.

Beclin‑1 suppresses gastric cancer progression by promoting apoptosis and reducing cell migration

“…Concomitantly, the autophagy-promoting activity in the MCF7 breast cancer cell line following transfection with Beclin-1 was observed to inhibit MCF7 proliferation, clonogenicity and tumorigenesis (10). A previous in vivo study demonstrated that mice with inactivated or deleted Beclin-1 were susceptible to tumors including lymphoma, lung cancer and liver cancer (11,12).…”

“…Concomitantly, the autophagy-promoting activity in the MCF7 breast cancer cell line following transfection with Beclin-1 was observed to inhibit MCF7 proliferation, clonogenicity and tumorigenesis (10). A previous in vivo study demonstrated that mice with inactivated or deleted Beclin-1 were susceptible to tumors including lymphoma, lung cancer and liver cancer (11,12).Beclin-1 modulates cancer initiation and progression by affecting a wide range of pathological events, including extracellular matrix degradation, epithelial-to-mesenchymal transition, tumor angiogenesis and alterations to the tumor microenvironment (13). However, the effect of Beclin-1 in cancer development is complex, as a number of reports have indicated the pro-neoplastic and anti-neoplastic functions for Beclin-1, as reviewed by Ozpolat and Benbrook (14).…”

Autophagy regulation in the development and treatment of breast cancer

“…Additionally, it may also contribute to breast cancer development in a manner independent of genotoxic stress and genomic instability through the induction of ER stress. Based on a study of Kongara et al [32] in 2010, autophagy plays a role in p62-dependent keratin 8 homeostasis in mammary epithelial cells and low Beclin-1 Figure 3. Autophagy and some of its regulatory pathways Binding of insulin or growth factors to the insulin receptor triggers the PI3K pathway, converting PIP2 into PIP3 that recruits PDK1 and Akt to the plasma membrane.…”

Cytokeratin 18 (CK18) and CK18 Fragments for Detection of Minimal Residual Disease in Colon Cancer Patients

“…Similarly, the keratin cytoskeleton in mammary epithelial cells disintegrates under metabolic stress of glucose and oxygen deprivation, which mimicks the tumor microenvironment (Nelson et al, 2004) Phosphorylation of CKs regulates their distribution into an insoluble filamentous cytoskeletal fraction and a soluble cytosolic hyperphosphorylated pool (Omary et al, 2006) and plays a role in CK ubiquitination and turnover by the proteasome (Ku & Omary, 2000;Jaitovich et al, 2008) and, likely, by autophagy (Kongara et al, 2010). CKs released from proliferating or necrotic/apoptotic cells are useful markers for prediction of tumor progression/recurrence or response to therapy (Linder, 2007).…”