Fig. 2

Core autophagy-dependent cell death signaling pathways in triple negative breast cancer (TNBC). Autophagy is a complex regulation process involving many upstream signaling pathways. Mammalian target of rapamycin (mTOR) is a negative regulator of autophagy, which is composed of mammalian target of rapamycin complex (mTORC) 1 and mTORC2. Among them, mTORC1 is the main autophagy regulator and phosphatidylinositol 3 kinase complex 1 (PI3KC1)-protein kinase B (Akt)-mTORC1 pathway inhibits the occurrence of autophagy. P53 pathway negatively regulates mTOR pathways to promote autophagy. When mTORC1 is inhibited, it can indirectly activate unc-51-like kinase 1 (ULK1) complex (including ULK1, autophagy associated protein (ATG) 101, ATG13, and focal adhesion kinase interacting protein of 200 kDa (FIP200)). ULK1 complex is closely related to Beclin1, and ULK1 can phosphorylate ATG14, which promotes the binding of Beclin1 to vacuolar protein sorting 34 (VPS34) and ultimately participates in the regulation of autophagy. Forkhead box O (FoxO) had been shown to regulate autophagy by transcriptional dependent mechanism. P62 can bind light chain 3 (LC3)-labeled autophagosomes to substrates, promote the combination of substrates and autophagosomes, and promote the occurrence of autophagy. Additionally, the inhibiting of Ras-Raf-MAPK pathway and NF-κB pathway could also regulate autophagy. Abbreviations: AKT: Protein kinase B; ATG: Autophagy associated protein; ERK: Extracellular signal-regulated kinase; FIP200: Focal adhesion kinase interacting protein of 200 kDa; FoxO: Forkhead box O; LC3: Light chain 3; MEK: Mitogen-activated protein kinase kinase; mTORC1: Mammalian target of rapamycin complex 1; PI3KC1: Phosphatidylinositol 3 kinase complex 1; ULK1: Unc-51-like kinase 1; Vps34: Vacuolar protein sorting 34