Mechanisms of endocrine resistance in breast cancer: an overview of the proposed roles of noncoding RNA

Abstract

Endocrine therapies such as tamoxifen and aromatase inhibitors are the standard treatment options for estrogen receptor-positive breast cancer patients. However, resistance to these agents has become a major clinical obstacle. Potential mechanisms of resistance to endocrine therapies have been identified, often involving enhanced growth factor signaling and changes in the expression or action of the estrogen receptor, but few studies have addressed the role of noncoding RNA (ncRNA). Two important types of ncRNA include microRNA (miRNA) and long noncoding RNA (lncRNA). miRNAs are small RNA molecules that regulate gene expression via translational inhibition or degradation of mRNA transcripts, while lncRNAs are larger RNA molecules that have been shown to play a role in multiple cellular maintenance functions such as protein scaffolding, chromatin looping, and regulation of mRNA stability. Both miRNA and lncRNA have recently impacted the field of breast cancer research as important pieces in the mechanistic puzzle of the genes and pathways involved in breast cancer development and progression. This review serves as an overview of the roles of miRNA and lncRNA in breast cancer progression and the development of endocrine resistance. Ideally, future experiments in the field should include identification of ncRNAs that could be potential therapeutic targets in endocrine-resistant tumors, as well as ncRNA biomarkers that facilitate more tumor-specific treatment options for endocrine-resistant breast cancer patients.

Figure 1

Mechanisms of endocrine resistance in breast cancer cells. (A) Mechanisms of tamoxifen (TAM) resistance may involve the loss of estrogen receptor (ER) alpha expression, which can be achieved by methylation of CpG islands or histone deacetylase activity in the ESR1 promoter. Tamoxifen-resistant growth is also stimulated by the upregulation of growth factor signaling pathways (HER2, IGFR1, and FGFR1) and subsequent activation of the mitogen-activated protein kinase (MAPK) cascade or phosphoinositide 3-kinase (PI3K) pathway. Finally, tamoxifen has even been shown to stimulate the growth of breast cancer cells when bound to certain coactivators, such as AIB1, and this is especially true in HER2-expressing cells. (B) The mechanisms of aromatase inhibitor (AI) resistance share similarities with tamoxifen resistance, especially in terms of growth factor pathway upregulation. The enhanced activity of growth factors such as MAPK can result in estrogen-independent phosphorylation and activation of ERα. In addition to growth factor signaling, interferon response genes and anti-apoptotic proteins have also been shown to have increased expression in AI-resistant cells. AIB1, amplified in breast cancer 1; FGFR1, fibroblast growth factor receptor 1; HER2, human epidermal growth factor receptor 2; IGFR1, insulin-like growth factor receptor 1.

Figure 2

Standard pathway by which microRNAs are processed and loaded onto RISC to regulate gene expression. Regulation of microRNA (miRNA) expression is controlled at the miRNA promoter by transcription factors (TF) and nuclear receptors (NR). After transcription, the pri-miRNA is processed inside the nucleus by Drosha and DGCR8 to form pre-miRNA – a hairpin miRNA. Exportin 5 exports the pre-miRNA from the nucleus into the cytoplasm where it gets cleaved further by Dicer, resulting in a short double-strand piece of RNA. These strands are separated into the passenger strand, which often gets degraded, and the mature strand, which is loaded onto RNA-induced silencing complex (RISC) for action on target mRNA. If the seed sequence (base pairs 2 to 7) of the mature miRNA is complementary to the mRNA, the transcript is degraded. However, if there is not perfect complementarity between the miRNA seed sequence and its target mRNA, the result is inhibition of translation. DGCR8, DiGeorge syndrome chromosomal region 8.

Figure 3

Location of long noncoding RNAs in the genome and roles of long noncoding RNAs in regulation of cellular processes. (A) Long noncoding RNA (lncRNA) genes reside in various genomic locations, such as in the promoters, enhancers, introns, or anti-sense coding regions of genes, and can also be in their own stand-alone position in the genome. These lncRNA genes sometimes contain small RNA genes, like microRNA (miRNA), that are spliced out of the lncRNA after transcription. (B) The actions of lncRNAs affect many cellular processes. lncRNAs may serve as scaffolds to bring nuclear receptors in contact with promoters of their target genes via chromatin looping, or they may recruit an epigenetic modifier to the chromatin. They can also bind proteins, such as transcription factors, to prevent their binding to DNA – similar to their mechanism of miRNA inhibition. Among the effects lncRNAs have on mRNA, translational activation and maintenance of mRNA stability are also important.

Figure 4

Role of microRNA in endocrine resistance. microRNAs (miRNAs) that regulate the growth, survival, apoptosis, epithelial-to-mesenchymal transition (EMT), and metastasis of breast cancer cells are implicated in the loss of responsiveness to endocrine therapies. miRNAs that are upregulated in endocrine resistance (red) could potentially be targets of RNA interference therapies, while miRNAs that are downregulated in endocrine resistance (green) could be targets of a replacement therapy in endocrine-resistant breast tumors. (A) miRNAs involved in tamoxifen resistance. (B) miRNAs involved in aromatase inhibitor (AI) resistance. Bim, Bcl-2-like 11; EGFR, epidermal growth factor receptor; ER, estrogen receptor; E2, 17β-estradiol; FGFR1, fibroblast growth factor receptor 1; HER2, human epidermal growth factor receptor 2; IGFR1, insulin-like growth factor receptor 1; MAPK, mitogen-activated protein kinase; MTDH, metadherin; PI3K, phosphoinositide 3-kinase; PTEN, phosphatase and tensin homolog; TGFR1β, transforming growth factor beta receptor 1; ZEB1/2, zinc finger E box-binding homeobox 1/2.