MicroRNA regulation of cancer stem cells in the pathogenesis of breast cancer

Abstract

Breast cancer is the most common cancer among women and accounts for 30% of all female malignancies worldwide. Breast cancer stem cells (BCSCs) are a small population of breast cancer cells that exhibit multiple characteristics including differentiation capacity, self-renewal and therapeutic resistance. Recently, BCSCs have attracted attention due to their modulation of breast tumor behaviors and drug resistance. miRNAs are small noncoding mRNAs involved in virtually all biological processes, including stem cell development, maintenance and differentiation. In breast cancer, miRNAs appear to be multi-faceted since they can act as either suppressors or oncogenes to regulate breast cancer progression. This review summarizes the critical roles of miRNAs in regulating multiple signaling pathways such as Wnt/β-catenin, Notch, PI3K/AKT/mTOR, BMI-1 and STAT3 that are important for the BCSC maintenance.

Keywords: Breast cancer; Breast cancer stem cell (BCSC); Self-renewal; Therapeutic resistance; miRNA.

Fig. 1

miRNAs act as suppressors or oncomiRs in BCSC maintenance. miRNAs can both act as suppressors (red background) or oncomiRs (green background) to influence BCSC activities independently of known signaling pathways (left panel). On the other hand, some miRNAs can be placed into well-defined signaling pathways (right panel, different color backgrounds) by positively or negatively regulating the characteristics and development of BCSCs such as self-renewal or chemoresistance capacities

Fig. 2

miRNA-mediated regulation of BCSCs via targeting the Wnt/β-catenin signaling pathway. a “Wnt off”. In the absence of Wnt ligands, the destruction complex (Axin-1, GSK-3β, APC, CX1α) is formed. β-catenin is phosphorylated by the destruction complex, thereby targeting it to be degraded by the β-TrCP-mediated ubiquitin proteasome system. b “Wnt on”. Wnt ligands bind to the Frizzled/Lrp 5/6 receptors, thus leading to Dvl phosphorylation. Phosphorylated Dvl recruits Axin to the membrane, which destroys the destruction complex and prevents the phosphorylation of β-catenin. Thus, β-catenin accumulates in the cytoplasm and finally moves into the nucleus, where it interacts with TCF4/LEF and/or co-activators and promotes the transcription of Wnt target genes. The immediate targets of several miRNAs are marked

Fig. 3

miRNA-mediated regulation of BCSCs via targeting the Notch signaling pathway. The Notch signaling pathway is activated when Notch ligands on one cell interact with Notch receptors on an adjacent cell, resulting in the two consecutive cleavages of Notch receptors by ADAMs and γ-secretase, and the release of Notch receptor intracellular domain NICD into the cytoplasm. The released NICD is translocated into the nucleus and binds to CSL to initiate the Notch target genes’ expression. The immediate targets of related miRNAs are marked

Fig. 4

miRNA-mediated regulation of BCSCs via targeting the PI3K/AKT/mTOR signaling pathway. AKT is activated by various signals including RTKs, integrins, B and T cell receptors, cytokine receptors and GPCRs through PIP3 produced by PI3Ks. PIP3 interacts with the PH domain of AKT and recruits AKT to the cell membrane, allowing PDK1 to phosphorylate AKT-Thr308. mTOR acts both as a downstream effector and an activator of AKT by phosphorylating AKT-Ser473. Dually-phosphorylated AKT fully activates the PI3K/AKT/mTOR signaling pathway. The immediate targets of miRNAs are marked

Fig. 5

miRNA-mediated regulation of the BCSCs via targeting the BMI-1 signaling pathway. a To support self-renewal of stem cells by BMI-1 (a component of PRC1), PRC1 suppresses the expression of the Ink4a locus that encodes the p16^Ink4a and the p19^Arf genes by trimethylation of H3-K27 (H3K27me3) and ubiquitination of H2A-K119 (H2AK119Ub). The chromodomain of CBX binds to H3K27me3 and RING1 deposits monoubiquitin on H2AK119. b p16^Ink4a inhibits the phosphorylation of RB by the cyclin D/Cdk4/6 complex and E2F-dependent transcription of RB that finally inhibit cell cycle progression. p19^Arf causes high levels of p53 via preventing MDM2-mediated p53 degradation, which represses cell cycle progression and promotes apoptosis. The immediate targets of miRNAs are marked

Fig. 6

miRNA-mediated regulation of BCSCs via targeting the STAT3 signaling pathway. a STAT3 has six functional domains and two phosphorylation sites, as indicated. b STAT3 is mainly activated by Tyr705 phosphorylation within the SH2 domain, which leads to its dimerization. Activated STAT3 dimers interact with importins, translocate into the nucleus and activate target gene transcription by binding to the GAS motif of target genes. The immediate targets of miRNAs are marked