Abstract
Macroautophagy (herein referred to as autophagy) is a complex catabolic process characterized by the formation of double-membrane vesicles called autophagosomes. During this process, autophagosomes engulf and deliver their intracellular content to lysosomes, where they are degraded by hydrolytic enzymes. Thereby, autophagy provides energy and building blocks to maintain cellular homeostasis and represents a dynamic recycling mechanism. Importantly, the clearance of damaged organelles and aggregated molecules by autophagy in normal cells contributes to cancer prevention. Therefore, the dysfunction of autophagy has a major impact on the cell fate and can contribute to tumorigenesis. Breast cancer is the most common cancer in women and has the highest mortality rate among all cancers in women worldwide. Breast cancer patients often have a good short-term prognosis, but long-term survivors often experience aggressive recurrence. This phenomenon might be explained by the high heterogeneity of breast cancer tumors rendering mammary tumors difficult to target. This review focuses on the mechanisms of autophagy during breast carcinogenesis and sheds light on the role of autophagy in the traits of aggressive breast cancer cells such as migration, invasion, and therapeutic resistance.
Highlights
Amin Moosavi and Institute of Pathology, University of Bern, CH-3008 Bern, Switzerland; Graduate School for Cellular and Biomedical Sciences, University of Bern, CH-3012 Bern, Switzerland
The ATG8 homologs are cleaved (LC3-I, GABARAP-I) by the ATG4 protease followed by the conjugation with phosphatidylethanolamine (PE) (LC3-II, GABARAP-II) and incorporation into the isolation membrane (IM) via ATG5/12 /16L and ATG3/7 complexes, which leads to the elongation and closure of the autophagosome, thereby incorporating cytoplasmic content. (D,E) When in close proximity, autophagosomes and lysosomes fuse, and the cargo is degraded into cellular building blocks by lysosomal proteases via hydrolysis
In Triple negative breast cancers (TNBC), autophagy facilitates the secretion of interleukin 6 (IL6), which is important for the maintenance of breast cancer stem cells (BCSCs) and the activation of the oncogenic Signal Transducer And Activator Of Transcription 3 (STAT3) signaling pathway
Summary
Macroautophagy (hereafter referred to as autophagy) is a highly conserved catabolic control mechanism responsible for the bulk degradation of intracellular molecules and cytoplasmic organelles in a lysosome-dependent manner to maintain cellular homeostasis [1,2]. The ATG8 homologs are cleaved (LC3-I, GABARAP-I) by the ATG4 protease followed by the conjugation with phosphatidylethanolamine (PE) (LC3-II, GABARAP-II) and incorporation into the isolation membrane (IM) via ATG5/12 /16L and ATG3/7 complexes, which leads to the elongation and closure of the autophagosome, thereby incorporating cytoplasmic content. The entire catabolic process depends on a machinery of 16–20 core autophagy (ATG)related genes, which function in complexes at distinct steps of the autophagic pathway. The ATG8 homologs have autophagy independent functions, and the ATG8 ubiquitin-like conjugation system is important but not absolutely essential for the phagophore elongation and closure [8,9,10,13]. 3-Methyladenine (3-MA), ULK1- and VPS34 inhibitors that abrogate autophagy at early stages (initiation, nucleation), Chloroquine (CQ), Hydroxychloroquine (HCQ), Lys, and Bafilomycin A1 (Baf. A1) that inhibit late stages (fusion, degradation) by alkalizing the lysosomal lumen, hindering autophagosome—lysosome fusion and inhibiting lysosomal. The ablation of autophagy affects the integrity of stem and terminally differentiated cells and leads to cellular and organismal dysfunctions during embryonic development [23,24,25]
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