A vicious circle in breast cancer: The interplay between inflammation, reactive oxygen species, and microRNAs

Abstract

Breast cancer (BC) is the most common cancer in women worldwide. This highly heterogeneous disease is molecularly stratified into luminal A, luminal B, HER2, triple-negative/basal-like, and normal-like subtypes. An important aspect in BC progression is the activation of inflammatory processes. The activation of CD8+/Th1, NK, and M1 tumor associated macrophages (TAMs), leads to tumor destruction. In contrast, an anti-inflammatory response mediated by CD4+/Th2 and M2 TAMs will favor tumor progression. Inflammation also stimulates the production of inflammatory mediators like reactive oxygen species (ROS). In chronic inflammation, ROS activates oxidative stress and endothelial dysfunction. In cancer, ROS plays a dual role with anti-tumorigenic and pro-tumorigenic effects in cell signaling pathways that control proliferation, survival, apoptosis, and inflammation. MicroRNAs (miRNAs), which are known to be involved in BC progression and inflammation, can be regulated by ROS. At the same time, miRNAs regulate the expression of genes modulating oxidative stress. In this review, we will discuss the interplay between inflammation, ROS, and miRNAs as anticancer and tumor promoter molecules in BC. A clear understanding of the role of miRNAs in the regulation of ROS production and inflammation, may lead to new opportunities for therapy in BC.

Keywords: breast cancer; inflammation; microRNAs; regulation; ros.

Figure 1

Effect of ROS in the miRNAs production. ROS can affect the production of miRNAs in various ways: modifying the miRNA biogenesis through the action on DGCR8 and DICER, altering the expression of transcription factors responsible for regulating their expression, or causing epigenetic alterations. Blue lines represent activation, red lines inhibition, and green lines bidirectional regulation.

Figure 2

Interplay between inflammation, ROS, and miRNAs in BC. To prevent the development/progression of BC, acute inflammation must be resolved. ROS and miRNAs play a key role in this inflammatory mechanism. Instead, during tumor development and tumor maintenance, chronic inflammation occurs. In this process, several inflammatory mediators are generated that deregulate ROS and miRNAs. Furthermore, the production of ROS and miRNAs are interconnected each other and with the inflammatory mediators during all steps of the carcinogenesis process in BC. Blue lines represent activation, red lines inhibition, green lines bidirectional regulation, and orange lines overexpression. (oncomiRs: oncogenic miRNAs, tsmiRs: tumor suppressor miRNAs).