GPER1 and microRNA: Two Players in Breast Cancer Progression

Abstract

Breast cancer is the main cause of morbidity and mortality in women worldwide. However, the molecular pathogenesis of breast cancer remains poorly defined due to its heterogeneity. Several studies have reported that G Protein-Coupled Estrogen Receptor 1 (GPER1) plays a crucial role in breast cancer progression, by binding to estrogens or synthetic agonists, like G-1, thus modulating genes involved in diverse biological events, such as cell proliferation, migration, apoptosis, and metastasis. In addition, it has been established that the dysregulation of short sequences of non-coding RNA, named microRNAs (miRNAs), is involved in various pathophysiological conditions, including breast cancer. Recent evidence has indicated that estrogens may regulate miRNA expression and therefore modulate the levels of their target genes, not only through the classical estrogen receptors (ERs), but also activating GPER1 signalling, hence suggesting an alternative molecular pathway involved in breast tumor progression. Here, the current knowledge about GPER1 and miRNA action in breast cancer is recapitulated, reporting recent evidence on the liaison of these two players in triggering breast tumorogenic effects. Elucidating the role of GPER1 and miRNAs in breast cancer might provide new tools for innovative approaches in anti-cancer therapy.

Keywords: CAFs; GPER1; breast cancer; estrogens; miRNAs; microRNAs.

Figure 1

Schematic representation of miRNA synthesis, as explained in the text. Abbreviations: RNA Pol II or III: RNA Polimerase II or III; Drosha: DGCR8: DiGeorge syndrome critical region gene 8; XOP5: Exportin 5; RISC complex: RNA-induced silencing complex.

Figure 2

Schematic representation of GPER1 involvement in the regulation of miRNA expression. Ligand-binding to GPER1 leads to activation of SRC through the β and γ subunits of the G protein. The complex SRC tyrosine kinase-SHC adapter protein triggers the EGFR transactivation, which, in turn, stimulates downstream pathways, like PI3K, MAPKs and PKCδ. In addition, GPER activation stimulates the activity of AC through the Gα subunit, leading to the PKA-mediated increase of CREB. Both signalling may trigger the expression of specific TFs involved in miRNA transcription. In the nucleus miRNAs are processed and exported in cytoplasm, where they become mature miRNAs. SRC: steroid receptor coactivator; EGFR: epidermal growth factor receptor; PI3K: phosphatidylinositol 3-kinase; PKCδ: phospho-kinase C delta; AC: adenylyl cyclase; PKA: phospho-kinase A; CREB: cAMP response element-binding protein; TFs: transcription factors. Further abbreviations are addressed in the text.