Obesity as a Risk Factor for Breast Cancer-The Role of miRNA

Abstract

Breast cancer (BC) is the most common cancer diagnosed among women in the world, with an ever-increasing incidence rate. Due to the dynamic increase in the occurrence of risk factors, including obesity and related metabolic disorders, the search for new regulatory mechanisms is necessary. This will help a complete understanding of the pathogenesis of breast cancer. The review presents the mechanisms of obesity as a factor that increases the risk of developing breast cancer and that even initiates the cancer process in the female population. The mechanisms presented in the paper relate to the inflammatory process resulting from current or progressive obesity leading to cell metabolism disorders and disturbed hormonal metabolism. All these processes are widely regulated by the action of microRNAs (miRNAs), which may constitute potential biomarkers influencing the pathogenesis of breast cancer and may be a promising target of anti-cancer therapies.

Keywords: breast cancer; estrogens; hypoxia; inflammation; metabolites; miRNA; obesity.

Figure 2

Estrogen Receptor signaling in breast epithelium cells and CAFs. Mechanisms of E2 action in cells can be divided into genomic action through binding to nuclear estrogen receptors ERα or Erβ, and non-genomic action by binding to GPER1 [131]. ERα and ERβ are ligand-activated transcription factors that mediate the effect of estrogens by binding with specific estrogen response elements (EREs) in promotors of target genes, which regulate the transcription of these genes [132]. ERα and Erβ, after activation by E2 binding, form homo- or heterodimers with each other. Activation of ERα promotes proliferation, tumor growth, and angiogenesis through the induction of expression of oncogenes like c-MYC, VEGF, or CCND1 [133,134,135]. The additional layer of the regulation of E2 genomic action is the interaction of ERs with various coactivators (CoA), such as transcription factor Sp1 (SP1), which modulate the binding of activated E2-ER complex with ERS [136]. Non-genomic action of E2 via binding to GPER1 leads to signal transduction through the G protein, which results in the synthesis of cAMP [137,138,139] and activation of downstream signaling pathways: phosphatidylinositol 3-kinase (PI3K), Akt kinase, Ca²⁺ signaling, and MAP kinases [140]. In breast tumors, estrogenic activation of GPER1 leads to the induction of proliferation, migration, or angiogenesis [141,142]. GPER1 is expressed also in breast cancer CAFs [143,144,145]. Activation of GPER1 signaling may lead to an increase in CAFs proliferation rate or migration by induction oncogenes expressions like c-Fos or Cyclin D1 (CCND1) [146]. Additionally, Lappano et al. demonstrated that estrogenic activation of GPER1 in CAFs promotes breast cancer development by increasing angiogenesis via activation of HIF1-α and VEGF expression [147]. The next mechanism, which leads to the promotion of breast cancer progression by CAFs via GPER1, is the induction of the expression of pro-inflammatory cytokine IL1B and its receptor ILR1 in breast cancer cells and CAFs [148]. The above figure was created with BioRender.com. Agreement number: TM24NOJWQS.

Figure 3

Obesity-related breast tumor initiation. The above figure was created with BioRender.com. Agreement number: KP24PM3RRF.

Figure 1

Classification of breast cancer. The above figure was created with BioRender.com. Agreement number: MV24QP1OWO.