Emerging role of necroptosis, pyroptosis, and ferroptosis in breast cancer: New dawn for overcoming therapy resistance

Abstract

Breast cancer (BC) is one of the primary causes of death in women worldwide. The challenges associated with adverse outcomes have increased significantly, and the identification of novel therapeutic targets has become increasingly urgent. Regulated cell death (RCD) refers to a type of cell death that can be regulated by several different biomacromolecules, which is distinctive from accidental cell death (ACD). In recent years, apoptosis, a representative RCD pathway, has gained significance as a target for BC medications. However, tumor cells exhibit avoidance of apoptosis and result in treatment resistance, which emphasizes further studies devoted to alternative cell death processes, namely necroptosis, pyroptosis, and ferroptosis. Here, in this review, we focus on summarizing the crucial signaling pathways of these RCD in BC. We further discuss the molecular mechanism and potentiality in clinical application of several prospective drugs, nanoparticles, and other small compounds targeting different RCD subroutines of BC. We also discuss the benefits of modulating RCD processes on drug resistance and the advantages of combining RCD modulators with conventional treatments in BC. This review will deepen our understanding of the relationship between RCD and BC, and shed new light on future directions to attack cancer vulnerabilities with RCD modulators for therapeutic purposes.

Keywords: Breast cancer; Drug resistance; Ferroptosis; Necroptosis; Pyroptosis.

Fig. 1

Molecular mechanism of necroptosis. ZBP1 and cell surface death receptors, such as FasRs, TNFR, IFN receptors, and TLRs, initiate necroptosis, and RHIM-containing downstream proteins bind to RIPK3. The necrosome is then developed, which causes cell lysis.

Fig. 2

Summary of several biological mechanisms involved in pyroptosis. A The mechanism of pyroptosis induced by granzymes and TNF-α/TRADD pathway. B Gram-negative bacteria induced cell death mediated by non-canonical pyroptotic pathways. C The canonical pyroptotic pathway induced by the interactions between PAMPs or DAMPs with PRRs. (Gzm A: Granzyme A; Gzm B: Granzyme B; PAMPs: pathogen-associated molecular patterns; DAMPs: damage-associated molecular patterns; PRRs: pattern recognition receptors; GSDMD-CT: GSDMD-C-terminus; and GSDME-CT: GSDME-C-terminus.).

Fig. 3

Defense pathways involved in ferroptosis. A In a glutathione (GSH)-dependent manner, GPX4 selectively catalyzes the loss of oxidative activity of lipid peroxides and protects cells against the threat of ferroptosis. B FSP1, a phospholipid peroxidation inhibitor that does not require GSH, changes the ubiquinone on the cell membrane into reduced ubiquinol, which can prevent peroxidation and ferroptosis. C GCH1 protects cells from ferroptosis through the antioxidant action of BH4. D DHODH inhibits ferroptosis by controlling the synthesis of dihydroubiquinone in the inner membrane of mitochondria.

Fig. 4

Summary of novel RCD modulators involved in BC treatment.