MicroRNA-mediated drug resistance in breast cancer

Abstract

Chemoresistance is one of the major hurdles to overcome for the successful treatment of breast cancer. At present, there are several mechanisms proposed to explain drug resistance to chemotherapeutic agents, including decreased intracellular drug concentrations, mediated by drug transporters and metabolic enzymes; impaired cellular responses that affect cell cycle arrest, apoptosis, and DNA repair; the induction of signaling pathways that promote the progression of cancer cell populations; perturbations in DNA methylation and histone modifications; and alterations in the availability of drug targets. Both genetic and epigenetic theories have been put forward to explain the mechanisms of drug resistance. Recently, a small non-coding class of RNAs, known as microRNAs, has been identified as master regulators of key genes implicated in mechanisms of chemoresistance. This article reviews the role of microRNAs in regulating chemoresistance and highlights potential therapeutic targets for reversing miRNA-mediated drug resistance. In the future, microRNA-based treatments, in combination with traditional chemotherapy, may be a new strategy for the clinical management of drug-resistant breast cancers.

Fig. 1

miRNA biogenesis and function. Mature miRNAs arise from a multistep process in which they are first transcribed by RNA polymerase II (RNA pol II) as a primary miRNA (pri-miRNA) transcript. After being cleaved in the nucleus by the RNAse III ribonuclease, Drosha, and its cofactor Pasha, the precursor miRNA (pre-miRNA) is exported to the cytoplasm by Exportin 5, where it is cleaved by a second RNAse III ribonuclease, Dicer. This 16- to 29-nucleotide-long miRNA duplex is then unwound to free the mature strand for incorporation into a RNA-induced silencing complex (RISC) and, based on sequence complementarity, directs translational repression or cleavage of its mRNA target by binding to either the 3′- or 5′-untranslated (UTR) regions