Endoplasmic reticulum stress targeted therapy for breast cancer

Abstract

Recurrence, metastasis, and drug resistance are still big challenges in breast cancer therapy. Internal and external stresses have been proven to substantially facilitate breast cancer progression through molecular and systemic mechanisms. For example, endoplasmic reticulum stress (ERS) results in activation of the unfolded protein response (UPR), which are considered an important cellular stress response. More and more reports indicate its key role in protein homeostasis and other diverse functions involved in the process of breast cancer progression. Therefore, therapies targeting the activation of ERS and its downstream signaling pathways are potentially helpful and novel tools to counteract and fight breast cancer. However, recent advances in our understanding of ERS are focused on characterizing and modulating ERS between healthy and disease states, and so little attention has been paid to studying the role and clinical application of targeting ERS in a certain cancer. In this review, we summarize the function and main mechanisms of ERS in different molecular types of breast cancer, and focus on the development of agents targeting ERS to provide new treatment strategies for breast cancer. Video Abstract.

Keywords: Anticancer drugs; Breast cancer; Endoplasmic reticulum stress; Signaling pathway; Unfolded protein response.

Fig. 1

Overview of the three sensors of UPR. Under normal conditions, the three proteins (IRE1a, PERK, and ATF6) bind to the molecular chaperone protein GRP78. While under stress conditions, GRP78 releases from the three sensors, resulting in their activation. Each activation pathway has a different signal transduction mechanism. IRE1α splices XBP1 mRNA to encode for the transcription factor XBP1s, which promotes the expression of genes involved in the protein folding and erase induce and add in ERAD. PERK undergoes oligomerization and auto-phosphorylation which then promotes the phosphorylation of phosphorylate eIF2a, leading to general translational attenuation while selectively activating ATF4. ATF6 is transported from the endoplasmic reticulum to the Golgi apparatus where it undergoes S1P and S2P protease cleavage, which releases the active form of ATF6

Fig. 2

UPR Signaling in ERα+ BC. In ERα+ BC cells, ERα can open IP3R calcium channels through PLCγ activity and then induce rapid anticipatory activation of the UPR. The IRE1α-XBP1s pathway is activated to reestablish ER homeostasis. PERK-eIF2α-ATF4 can be activated to induce expression of apoptosis genes, such as CHOP. PERK can also be activated to promote apoptosis through TNFα expression promoted by NF-κB. The drugs targeting ERS-associated signaling pathways in ER+ BC are listed. Red represents pathway inhibitors and green represents pathway activators

Fig. 3

UPR Signaling in HER2+ BC. In HER2+ BC cells, HER2 amplification can activate the UPR through the PERK-ATF4-CHOP-TRAIL-R2 pathway, and the PERK-ATF4-ZEB1-E-cadherin pathway can regulate cell apoptosis and migration. Meanwhile, HER2-mTOR signaling can activate the IRE1 pathway. The drugs targeting ERS-associated signaling pathways in HER2+ BC are listed. Green represents pathway activators

Fig. 4

UPR Signaling in TNBC. In TNBC cells, the IRE1α–XBP1s pathway can interact with HIF1α and c-MYC to participate in cell survival, angiogenesis, and invasion. Meanwhile, the PERK–eIF2α pathway activates either the peIF2α–ATF4 pathway or the transcription factor NRF2 to induce autophagy and redox control. The drugs targeting ERS-associated signaling pathways in TNBC are listed. Red represents pathway inhibitors and green represents pathway activators