miRNA clusters as therapeutic targets for hormone-resistant breast cancer

Abstract

MicroRNAs are small non-coding RNAs that typically inhibit the translation and stability of messenger RNAs, controlling genes involved in cellular processes such as inflammation, cell cycle regulation, stress response, differentiation, apoptosis, and migration. Not surprisingly, microRNAs are also aberrantly expressed in cancer and promote tumorigenesis by disrupting these vital cellular functions. In this review, we first broadly summarize the role of microRNAs in breast cancer and Estrogen Receptor alpha signaling. Then we focus on what is currently known about the role of microRNAs in anti-hormonal therapy or resistance to endocrine agents. Specifically, we will discuss key miRNAs involved in tamoxifen (miR-221/222, 181, 101, 519a, 301, 375, 342, 451, and the let-7 family), fulvestrant (miR-221/222, miR-200 family), and aromatase inhibitor (miR-128 and the let-7 family) resistance.

Keywords:

• microRNA
• breast cancer
• non-coding RNAs
• endocrine therapy
• endocrine therapy resistance
• tamoxifen
• fulvestrant
• aromatase inhibitor
• estrogen receptor

Key issues

• ER-positive breast cancer accounts for more than 70% of breast cancers.

• Hormonal therapy is a standard therapy for patients with ER-positive breast cancer. Three major types of hormonal therapy are currently available: tamoxifen, fulvestrant, and AIs.

• Hormonal therapy resistance is common, i.e. 30% to tamoxifen and 20% to AIs.

• ER and miRNAs are strongly inter-regulated. ER regulates the expression of numerous miRNAs transcriptionally and the expression of key components in miRNA biogenesis. At the same time, miRNAs regulate ER activity by translation inhibition, mRNA degradation, and targeting other proteins that cooperate with ER.

• miRNAs have been shown to be involved in the resistance to all types of hormonal therapy, and therefore, they are attractive therapeutic targets and markers.

Acknowledgement

The authors gratefully acknowledge the entire laboratory of Dr. Croce for helpful discussions and suggestions.

Financial & competing interests disclosure

The authors were supported by a grant from National Institutes of Health/National Cancer Institute U01-CA152758 received by CM Croce. DG Cheung was funded by NIH-NIGMS Grant T32-GM086252 and the OSU/HHMI Med into Grad Scholars Program. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.