microRNA, cell cycle, and human breast cancer

Abstract

The discovery of microRNAs as a novel class of gene expression regulators has led to a new strategy for disease diagnostics and therapeutics. Cell cycle, cell proliferation, and tumorigenesis are all regulated by microRNAs. Several general principles linking microRNAs and cancer have been recently reviewed; therefore, the current review focuses specifically on the perspective of microRNAs in control of cell cycle, stem cells, and heterotypic signaling, as well as the role of these processes in breast cancer. Altered abundance of cell cycle regulation proteins and aberrant expression of microRNAs frequently coexist in human breast cancers. Altered microRNA expression in breast cancer cell lines is associated with altered cell cycle progression and cell proliferation. Indeed, recent studies have demonstrated a causal role for microRNA in governing breast tumor suppression or collaborative oncogenesis. This review summarizes the current understanding of the role for microRNA in regulating the cell cycle and summarizes the evidence for aberrant microRNA expression in breast cancer. The new evidence for microRNA regulation by annotated genes and the involvement of microRNA in breast cancer metastasis are discussed, as is the potential for microRNA to improve breast cancer diagnosis and therapy.

Figure 1

miRNA–cell cycle regulation network. The miR-34 family is involved in cell cycle regulation by repressing E2F, cyclin D1, and cyclin E expression. miR-34 itself is a direct transcriptional target of p53. The miR-17/20 cluster is transcriptionally regulated by myc, E2Fs, and cyclin D1, and it in turn regulates E2F, pRb, and cyclin D1 expression at the translation level. miR-15/16 regulates cell cycle control by inhibiting cyclin D1, cyclin E, and CDK4/6.

Figure 2

miR-target regulatory loop. A: The miR-17/20 cluster, which is transcriptionally induced by E2F, in turn translationally represses E2F expression. B: AML1 transcriptionally inhibits miR-17/20 expression, and miR-17/20 inhibits AML1 translation. C: Myc induces the miR-17/20 cluster, and miR-17/20 inhibits myc expression. D: Cyclin D1 induces miR-17/20 expression, and miR-17/20 translationally inhibits cyclin D1 expression. E: OCT4 inhibits miR-145 expression, and miR-145 in turn inhibits OCT4 by 3′UTR binding. F: p53 transcriptionally induce the expression of the miR-34 family, and miR-34 negatively targets the downstream genes of p53.

Figure 3

miRNA regulation of breast cancer metastasis. A: Metastasis inhibitor miRs in breast cancer. B: Metastasis inducer miRs in breast cancer.