Nrf2 Modulation in Breast Cancer

Abstract

Reactive oxygen species (ROS) are identified to control the expression and activity of various essential signaling intermediates involved in cellular proliferation, apoptosis, and differentiation. Indeed, ROS represents a double-edged sword in supporting cell survival and death. Many common pathological processes, including various cancer types and neurodegenerative diseases, are inflammation and oxidative stress triggers, or even initiate them. Keap1-Nrf2 is a master antioxidant pathway in cytoprotective mechanisms through Nrf2 target gene expression. Activation of the Nfr2 pathway benefits cells in the early stages and reduces the level of ROS. In contrast, hyperactivation of Keap1-Nrf2 creates a context that supports the survival of both healthy and cancerous cells, defending them against oxidative stress, chemotherapeutic drugs, and radiotherapy. Considering the dual role of Nrf2 in suppressing or expanding cancer cells, determining its inhibitory/stimulatory position and targeting can represent an impressive role in cancer treatment. This review focused on Nrf2 modulators and their roles in sensitizing breast cancer cells to chemo/radiotherapy agents.

The pseudokinase NRBP1 activates Rac1/Cdc42 via P-Rex1 to drive oncogenic signalling in triple-negative breast cancer

“…For example, small molecules that block P-Rex1 function have been identified [39]. In addition, the important role of ROS in NRBP1/P-Rex1 signalling raises the possibility of targeting antioxidant pathways, such as those mediated by NRF2/KEAP1, in order to raise ROS levels above those compatible with cell survival [40]. Consequently, this newlyidentified NRBP1 signalling axis represents a potential target for precision treatment of TNBC, which urgently requires additional targeted therapeutic approaches.…”

Pharmacological Modulations of Nrf2 and Therapeutic Implications in Aneurysmal Subarachnoid Hemorrhage

“…Nrf2 contains 605 amino acids divided into seven domains (Neh1-7). Among them, the Neh2 domain at the N-terminal is the main regulatory domain [ 15 ]. The Neh2 domain includes seven lysine residues and two binding sites (ETGE and DLG motifs), which are the main binding sites with Keap1, and it participates in the ubiquitination regulation of Nrf2 [ 16 ].…”

“…Under normal conditions, Keap1 binds to the Neh2 domain of Nrf2 in the cytoplasm and promotes ubiquitin-dependent degradation, thereby maintaining Nrf2 at low levels and preventing constitutive activation of oxidative stress [ 9 ]. Each Kelch domain of the Keap1 homodimer is linked to the Nrf2 protein by a low-affinity DLG motif and a high-affinity ETGE motif, with the former having 1/100 of the affinity of the latter [ 15 ]. The hinge and latch hypothesis proposes that the ETGE binding site acts as a hinge, while the DLG binding site acts as a latch [ 16 ].…”

Phenylsulfonimide PPARα Antagonists Enhance Nrf2 Activation and Promote Oxidative Stress-Induced Apoptosis/Pyroptosis in MCF7 Breast Cancer Cells

“…A recent study showed that the Nrf2 overexpression promotes the proliferation and migration of MCF7 and MDA-MB-231 breast cancer cells [ 6 ]. In addition, Nrf2 has been identified as a key regulator in the chemotherapeutic resistance of MCF7 cells under hypoxia conditions [ 7 ]. Considering this, targeting proteins which in turn can modulate the Nrf2-related pathway could represent a novel potential treatment for drug resistance in BC cells.…”