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.
Highlights
Breast cancer is the most commonly diagnosed cancer in the United States and is the second leading cause of cancer death
In summary, there are numerous Noncoding RNA (ncRNA) shown to be involved in acquired resistance to endocrine therapies. ncRNAs provide an exciting avenue of gene regulation that has not yet been fully explored
As we uncover the miRNAs and long noncoding RNA (lncRNA) involved in specific disease states, such as resistance to breast cancer treatments, it will be possible to use these RNAs as both therapeutic targets and biomarkers
Summary
Breast cancer is the most commonly diagnosed cancer in the United States and is the second leading cause of cancer death. There are three US Food and Drug Administration-approved oral AIs in clinical use for the treatment of postmenopausal women with hormone receptor-positive breast cancer. These AIs can be divided into two categories: steroidal AIs (exemestane) and nonsteroidal AIs (anastrozole, letrozole). Estrogen receptor antagonists Targeting ERα using selective ER modulators and selective ER downregulators has been an effective treatment strategy for patients with ERα-positive hormonedependent breast cancer. Aromatase inhibitors While ER antagonists have played an important role in combating ERα-positive breast cancers for the past few decades, another class of therapies has emerged – AIs. The aromatase enzyme (a cytochrome P450 hemecontaining protein) is required for the synthesis of estrogen via aromatization of androgens such as testosterone [15]. Hypermethylation of CpG islands and histone deacetylase activity in the ESR1 promoter (Figure 1A) are similar to the absence of ERα because these can inactivate the gene so the cells express much less ERα [26]
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