MicroRNA Regulation of Human Breast Cancer Stem Cells

Abstract

MicroRNAs (miRNAs) are involved in virtually all biological processes, including stem cell maintenance, differentiation, and development. The dysregulation of miRNAs is associated with many human diseases including cancer. We have identified a set of miRNAs differentially expressed between human breast cancer stem cells (CSCs) and non-tumorigenic cancer cells. In addition, these miRNAs are similarly upregulated or downregulated in normal mammary stem/progenitor cells. In this review, we mainly describe the miRNAs that are dysregulated in human breast CSCs directly isolated from clinical specimens. The miRNAs and their clusters, such as the miR-200 clusters, miR-183 cluster, miR-221-222 cluster, let-7, miR-142 and miR-214, target the genes and pathways important for stem cell maintenance, such as the self-renewal gene BMI1, apoptosis, Wnt signaling, Notch signaling, and epithelial-to-mesenchymal transition. In addition, the current evidence shows that metastatic breast CSCs acquire a phenotype that is different from the CSCs in a primary site. Thus, clarifying the miRNA regulation of the metastatic breast CSCs will further advance our understanding of the roles of human breast CSCs in tumor progression.

Keywords: Bmi1; Wnt signaling; cancer stem cells; epithelial-to-mesenchymal transition (EMT); metastasis; microRNA.

Figure 1

A schematic representation of the miRNA clusters dysregulated in human breast CSCs. The miRNAs sharing the same seed sequence (nucleotides from two to seven) are marked by the same color. The mammalian miR-200 clusters are expressed as two separate polycistronic pri-miRNA transcripts. The miRNAs coded in the miR-200b-200a-429, miR-200c-141 and miR-183-96-182 clusters are downregulated, and those in the miR-221-222 cluster are upregulated in the human breast CSCs. The arrows indicate the direction of the pri-miRNA transcription.

Figure 2

Regulation of cell cycle, apoptosis, and senescence by self-renewal factor Bmi1. Bmi1, a component of PRC1, is involved in the stem cell maintenance in multiple tissues and organs. PRC1 suppresses the Ink4a locus that encodes the p16^Ink4a and the p19^Arf genes through the specific biochemical histone modifications, such as the trimethylation of the H3-K27 (H3K27me3) and the ubiquitination of H2A-K119 (H2AK119Ub). The chromodomain of CBX binds to H3K27me3 and RING1 deposits monoubiquitin on H2AK119. In the absence of p16^Ink4a, the cyclin D/Cdk4/6 complex can phosphorylate RB, allowing the E2F-dependent transcription which leads to cell cycle progression. In the absence of p19^Arf, MDM2-mediated p53 degradation causes low p53 levels, thus preventing cell cycle arrest and apoptosis. In addition, the gradual accumulation of p16^Ink4a expression during physiological aging implicates that p16^Ink4a is involved in the regulation of senescence.

Figure 3

Targeting of the genes and pathways for stem cell maintenance by miR-200 family miRNAs. Expression of the miR-200 family miRNAs is downregulated in the breast CSCs and normal mammary stem/progenitor cells, and is upregulated in the more differentiated counterparts. The miR-200 family miRNAs are involved in the regulation stem cell functions by targeting the genes and pathways important for stem cell maintenance, such as self-renewal factor Bmi-1, the apoptosis signaling pathway, the canonical Wnt signaling pathway, EMT and the Notch signaling pathway.

Figure 4

Activation of the canonical Wnt signaling pathway by the breast CSC-specific miRNAs. The canonical Wnt signaling pathway is implicated in both stem cell self-renewal and cancer. The multiple miRNAs dysregulated in the breast CSCs, such as miR-142, miR-146, miR-200, and miR-141, cooperatively activate the Wnt signaling pathway by targeting or upregulating the expression of its components. The activation of the Wnt signaling pathway induces the transcription of the Wnt target genes, including miR-146 and miR-150. miR-150 enhances the proliferation of mammary epithelial cells. Upregulation of miR-146 further enhances the activity of the Wnt signaling pathway in a positive feedback manner.