Crosstalk between Oxidative Stress Signaling and HER2 Pathway in Breast Cancer

Abstract

About 20% of breast cancer patients overexpress the Human Epidermal growth factor Receptor-2 (HER2), also known as ErbB2. HER2overexpression is associated with enhanced tumor malignancy and its overexpression is related to specific target therapy against breast tumors and other cancers. HER2-mediated pathways in tumor cells act on behalf of the tumor conferring aggressive characteristics. Several reports demonstrated the occurrence of toxicity during the anti-HER2 therapy and this fact has been associated with the generation of reactive species and oxidative stress. However, the link between HER2 and oxidative stress signaling is still poorly understood. The aim of this review is to point out the interplay between oxidative stress and HER2 signaling in breast cancer. An overview regarding HER2 biology and oxidative stress pathways is provided with a special focus in studies that implicate on HER2-generation of reactive species and oxidative stress during trastuzumab-based treatments.

Discovery and Pharmacological Evaluation of STEAP4 as a Novel Target for HER2 Overexpressing Breast Cancer

“…However, despite these findings we are not aware of a published direct linkage between STEAP4 and HER2, necessitating further research on this topic. We hypothesize that in the inflammatory tumor microenvironment, STEAP4 and HER2+ are somehow interconnected with an unidentified direct or indirect mechanism involving inflammatory cytokines that eventually contributes to increased intracellular iron accumulation, which in turn could lead to enhanced oxidative stress promoting HER2+ BC progression ( 41 , 74 ). Further proteomic and gene expression profiling studies in lapatinib and/or DFP treated, untreated and STEAP4-silenced HER2+ BC cells need investigation in order to identify key signaling differences, direct interacting partners and pathway enrichment correlating with STEAP4 expression.…”

NF-kappaB Regulates Redox Status in Breast Cancer Subtypes

“…Oxidative stress (OS) is an indispensable condition to ensure genomic instability in cancer cells [ 26 , 27 , 28 , 29 ]. Thus, a redox imbalance represents an important factor for BC carcinogenesis and prognosis and is frequently associated with pro-inflammatory conditions [ 24 , 30 , 31 , 32 ]. Although a correlation between NF-κB and OS has been reported in cancer [ 33 , 34 ], its role in BC intrinsic groups has not been reported to date.…”

“…HER2-amplified cells demonstrated an intermediary oxidative profile when compared to the other BC cells investigated at basal levels, potentially because HER2 overexpression attenuates OS in breast cancer [ 32 , 49 ]. The 24-h NF-κB inhibition simultaneously augmented the thiol content and reduced lipid peroxidation, revealing a role for this transcription factor in the regulation of the OS of HER2-amplified cells.…”

Mecanismos de proliferação celular dependentes da atividade do coativador - 1 de receptor ativado por proliferadores de peroxissoma gama (PGC-1)

“…Durante a progressão do câncer de mama, as ciclinas, juntamente com ciclinas dependentes de quinases (CDKs), podem promover a progressão do ciclo celular através de estágios específicos (denominados "checkpoints") por regular a expressão de fatores de transcrição e componentes chave do ciclo celular (Zafonte et al, 2000). Além do mais, a sinalização induzida por HER2 pode por si só influenciar a expressão de diferentes ciclinas envolvidas no controle do ciclo celular (Victorino et al, 2014a;Dan et al, 2002;Janes et al, 1994).…”

“…Os guias atuais definem 4 subtipos moleculares: luminal A, luminal B, HER2-positivo e triplo-negativo (Senn, 2013;Untch et al, 2013), conforme Tabela 1 abaixo. Azambuja et al, 2009, Panis et al, 2012Panis et al, 2011a;Panis et al, 2011b, Victorino et al, 2014a. Nesse contexto, a busca ativa por novos marcadores moleculares e alvos terapêuticos ainda se faz extremamente necessária.…”