Targeting Autophagy in Breast Cancer

Abstract

Breast cancer is a heterogeneous disease consisting of different biological subtypes, with differences in terms of incidence, response to diverse treatments, risk of disease progression, and sites of metastases. In the last years, several molecular targets have emerged and new drugs, targeting PI3K/Akt/mTOR and cyclinD/CDK/pRb pathways and tumor microenvironment have been integrated into clinical practice. However, it is clear now that breast cancer is able to develop resistance to these drugs and the identification of the underlying molecular mechanisms is paramount to drive further drug development. Autophagy is a highly conserved homeostatic process that can be activated in response to antineoplastic agents as a cytoprotective mechanism. Inhibition of autophagy could enhance tumor cell death by diverse anti-cancer therapies, representing an attractive approach to control mechanisms of drug resistance. In this manuscript, we present a review of autophagy focusing on its interplay with targeted drugs used for breast cancer treatment.

Keywords: ACD; ATG; Chloroquine; Hydroxychloroquine; autophagy; breast cancer.

Figure 1

The Unc-51 like autophagy activating kinase (ULK1) serine threonine kinase complex, involving ULK1, FIP200, and ATG13, acts in the initiation process, phosphorylating multiple downstream factors. Then, the complex involving Beclin1, VPS34, a class III phosphatidylinositol-3-kinase (PI3K) and ATG14 acts in autophagosome nucleation step. During the maturation step, the ATG7 and ATG10 conjugate ATG5 to ATG12, and ATG7 and ATG3 conjugate microtubule-associated protein 1 light chain 3 (LC3) (ATG8) to the lipid phosphatidylethanolamine (PE). The ATG5-ATG12 conjugate forms a complex with ATG16, and the ATG5-ATG12-ATG16 complex gets anchored onto phosphoinositol 3-phosphate generated by VPS34 on emerging autophagosomal membranes through WD repeat domain, phosphoinositide-interacting 2b (WIPI-2b). The complex is efficient for the LC3 conjugation system. LC3 is first conjugated with PE. ATG4 plays a role in lipoxidating LC3 to LC3-I and exposes the C-terminal glycine of LC3 for the subsequent conjugation of PE. PE is conjugated to the C-terminal glycine of LC3-I, and this conjugation needs to be catalyzed by the E1-like enzyme ATG7 and the E2-like enzyme ATG3. The autophagosomal membrane is conjugated with LC3-PE. During fusion with the lysosome, the LC3-II bound to the outer membrane is cleaved and recycled by ATG4, while LC3-PE associated with the inner membrane is degraded by lysosomal proteases along with the cargo of the autophagosome, thus recycling amino acids, fatty acids, and nucleotides.