The role of non-coding RNAs in the regulation of stem cells and progenitors in the normal mammary gland and in breast tumors

Abstract

The outlook on stem cell (SC) biology is shifting from a rigid hierarchical to a more flexible model in which the identity and the behavior of adult SCs, far from being fixed, are determined by the dynamic integration of cell autonomous and non-autonomous mechanisms. Within this framework, the recent discovery of thousands of non-coding RNAs (ncRNAs) with regulatory function is redefining the landscape of transcriptome regulation, highlighting the interplay of epigenetic, transcriptional, and post-transcriptional mechanisms in the specification of cell fate and in the regulation of developmental processes. Furthermore, the expression of ncRNAs is often tissue- or even cell type-specific, emphasizing their involvement in defining space, time and developmental stages in gene regulation. Such a role of ncRNAs has been investigated in embryonic and induced pluripotent SCs, and in numerous types of adult SCs and progenitors, including those of the breast, which will be the topic of this review. We will focus on ncRNAs with an important role in breast cancer, in particular in mammary cancer SCs and progenitors, and highlight the ncRNA-based circuitries whose subversion alters a number of the epigenetic, transcriptional, and post-transcriptional events that control "stemness" in the physiological setting.

Keywords: breast cancer; cancer stem cell; lncRNA; mammary gland; miRNA; non-coding RNA; stem cell.

FIGURE 1

Genome organization and biogenesis of microRNAs (miRNAs). miRNA genes are interspersed in the genome with various possible locations as depicted on top. The figure summarizes the steps of the canonical miRNA biogenetic pathway, including the production of a primary transcript (pri-miRNA) by RNA polymerase II or III (Pol II or III), nuclear and cytoplasmic processing, loading into the miRISC complex, and the degradation of mature miRNAs. The function of miRNAs is exerted in the cytosol at the level of the miRISC, where miRNAs induce target gene repression by various mechanisms, including inhibition of protein synthesis and mRNA destabilization.

FIGURE 2

Genomic organization and functions of long ncRNAs (lncRNAs). lncRNA genes are interspersed in the genome in various possible locations in relation to protein coding transcripts, such as (i) overlapping; (ii) intergenic; or (iii) divergent transcripts. Transcription of lncRNAs follows the same rules as for protein coding genes and is executed by RNA Pol II. Genomic features associated with transcription [such as CpG island (green boxes) or histone marks (histone H3 “K4K36 domains”)] provide a useful strategy to identify expressed lncRNAs. Functions of lncRNAs are executed by multiple modes of action and can occur both in the nucleus and in the cytosol. The figure shows some examples of nuclear or cytoplasmic functions of some known lncRNAs.

FIGURE 3

Hierarchical organization of the mammary gland and breast cancer subtypes. The figure depicts the epithelial components of the mammary gland. In the lower part, the characteristics of normal and cancer stem cells are summarized. (SC, stem cells; PC, progenitors; DC, differentiated cells).

FIGURE 4

microRNAs and lncRNAs control stemness and differentiation by interacting with signaling and transcriptional/epigenetic networks. The figure summarizes the activity of the main miRNAs and lncRNAs involved in the control of normal or cancer mammary SCs together with signaling networks (cytosol) and the transcriptional/epigenetic framework (nucleus) to which they belong or that they regulate. Straight and dashed arrows refer to direct or indirect interaction/regulation, respectively. Red lines mark inhibitory interactions. The activity of transcriptional factors (TFs) and chromatin regulators (CRs), cited in the text and involved in the control of stemness and differentiation, are also shown.