Non-Coding RNAs Modulating Estrogen Signaling and Response to Endocrine Therapy in Breast Cancer

Abstract

The largest part of human DNA is transcribed into RNA that does not code for proteins. These non-coding RNAs (ncRNAs) are key regulators of protein-coding gene expression and have been shown to play important roles in health, disease and therapy response. Today, endocrine therapy of ERα-positive breast cancer (BC) is a successful treatment approach, but resistance to this therapy is a major clinical problem. Therefore, a deeper understanding of resistance mechanisms is important to overcome this resistance. An increasing amount of evidence demonstrate that ncRNAs affect the response to endocrine therapy. Thus, ncRNAs are considered versatile biomarkers to predict or monitor therapy response. In this review article, we intend to give a summary and update on the effects of microRNAs (miRNAs), long non-coding RNAs (lncRNAs) and circular RNAs (circRNAs) on estrogen signaling in BC cells, this pathway being the target of endocrine therapy, and their role in therapy resistance. For this purpose, we reviewed articles on these topics listed in the PubMed database. Finally, we provide an assessment regarding the clinical use of these ncRNA types, particularly their circulating forms, as predictive BC biomarkers and their potential role as therapy targets to overcome endocrine resistance.

Chemotherapy-induced exosomal circBACH1 promotes breast cancer resistance and stemness via miR-217/G3BP2 signaling pathway

“…A latest study indicated that endocrine resistance was transcriptomic regulated by differentially expressed lncRNA, circRNA, microRNA and mRNA in endocrine resistant breast cancer cells compared with endocrine sensitive MCF-7 [ 58 ]. It has been demonstrated that circRNAs act as miRNA sponge to regulate endocrine resistance [ 24 , 59 ]. In our study, we demonstrated that PTX-induced exosomal circBACH1 regulated stemness and migration of BC cells by sponging miR-217 to upregulate the expression of G3BP2, which provided a new therapeutic target for PTX-resistance and progression of BC via circBACH1/miR-217/G3BP2 axis.…”

Circular RNAs in breast cancer diagnosis, treatment and prognosis

“…Increasing studies have claimed that circRNAs have important functions in endocrine resistance and that they are considered predictive biomarkers to monitor the response to endocrine therapy. Moreover, they have great potential as therapeutic targets to overcome resistance to endocrine therapy [ 73 ]. CircPVT1 is elevated in ERα-positive breast cancer and could promote resistance to endocrine therapy by sponging miR-181a-2-3p to stabilize the expression of ESR1 and promote the activity of estrogen/ERα target genes, while targeting circPVT1 could resensitize breast cancer cells to tamoxifen treatment [ 58 ].…”

Construction of ceRNA networks in endocrine therapy resistance model systems

“…We propose that an integrated RNA network analysis to find common genes/pathways using cell lines representing various forms of ETR could be useful in designing biomarkers that indicate potential ETR, independent of the initiating event. It is clear that the expression of not only the coding mRNAs but also the non-coding genome influences ETR (11). While the long non-coding RNAs (lncRNAs) regulate mRNA expression by cis-/trans-regulation at the transcriptional level, microRNAs (miRNAs) work post-transcriptionally to interfere with the translation of the protein encoded by its target mRNA (12).…”

“…Clearly, the ratio of mRNA:lncRNA:miRNA will tend to determine the final expression levels of a gene/protein. Typically, co-expression and competing endogenous RNA networks are used to understand the complex RNA regulation and they have been successfully used to segregate ER+ and ER-tumors, understand the response to Tamoxifen in cancer patients and generate lncRNA or miRNA signatures (11,(14)(15)(16)(17). ceRNA networks for Tam sensitive and TAMR cells have been constructed previously and MCF7 derived LLC3 and LCC9 Tam resistant cells (18,19).…”