The Evolving Role of Ferroptosis in Breast Cancer: Translational Implications Present and Future

Abstract

Breast cancer (BC) is the most common malignancy among women worldwide. The discovery of regulated cell death processes has enabled advances in the treatment of BC. In the past decade, ferroptosis, a new form of iron-dependent regulated cell death caused by excessive lipid peroxidation has been implicated in the development and therapeutic responses of BC. Intriguingly, the induction of ferroptosis acts to suppress conventional therapy-resistant cells, and to potentiate the effects of immunotherapy. As such, pharmacological or genetic modulation targeting ferroptosis holds great potential for the treatment of drug-resistant cancers. In this review, we present a critical analysis of the current understanding of the molecular mechanisms and regulatory networks involved in ferroptosis, the potential physiological functions of ferroptosis in tumor suppression, its potential in therapeutic targeting, and explore recent advances in the development of therapeutic strategies for BC.

Comprehensive analysis regarding the prognostic significance of downregulated ferroptosis-related gene AKR1C2 in gastric cancer and its underlying roles in immune response

“…Ferroptosis is a cell death form that is strongly correlated with lipid peroxidation and special modulators [ 26 ]. The cysteine metabolism and GPX4 inactivation have been proved to play important roles in ferroptosis [ 27 ]. Recent studies showed that it takes part in the process of some human diseases and cancers [ 28 ].…”

Inducing ferroptosis has the potential to overcome therapy resistance in breast cancer

“…Morphologically, ferroptotic cells show significant changes in mitochondrial morphology, with mitochondrial contraction, rupture of the outer mitochondrial membrane (OMM), and enlarged mitochondrial cristae. In the absence of swelling or contraction of cells in necrosis and apoptosis, neither nuclear changes nor chromatin condensation ( 3 , 66 , 67 ).…”

“…The Tricarboxylic Acid (TCA) cycle and electron transport chain (ETC) action are necessary for mitochondria to produce sufficient ROS via oxidative phosphorylation (OXPHOS) ( 84 , 85 ). Ferroptotic cells undergo significant changes in mitochondrial morphology with mitochondrial contraction, rupture of the OMM, and enlarged mitochondrial cristae ( 3 , 67 ). Robustaflavone A (RF-A) promotes Voltage-dependent anion-selective channel protein 2 (VDAC2) expression and ubiquitinated degradation, inducing the breakdown of mitochondrial functional systems, lipid peroxidation and ROS production, ultimately leading to ferroptosis in breast cancer cells.…”

Identification of Ferroptosis-Related Prognostic Signature and Subtypes Related to the Immune Microenvironment for Breast Cancer Patients Receiving Neoadjuvant Chemotherapy

“…Ferroptosis has the characteristics of inhibiting chemoresistance and enhancing antitumor immunity ( 18 ), which may be a potential strategy to overcome the drug resistance mechanism of traditional cancer treatments ( 12 ). Previous studies prove the feasibility of ferroptosis-related prognostic markers to predict overall survival and immune characteristics.…”