Keeping abreast with long non-coding RNAs in mammary gland development and breast cancer

Abstract

The majority of the human genome is transcribed, even though only 2% of transcripts encode proteins. Non-coding transcripts were originally dismissed as evolutionary junk or transcriptional noise, but with the development of whole genome technologies, these non-coding RNAs (ncRNAs) are emerging as molecules with vital roles in regulating gene expression. While shorter ncRNAs have been extensively studied, the functional roles of long ncRNAs (lncRNAs) are still being elucidated. Studies over the last decade show that lncRNAs are emerging as new players in a number of diseases including cancer. Potential roles in both oncogenic and tumor suppressive pathways in cancer have been elucidated, but the biological functions of the majority of lncRNAs remain to be identified. Accumulated data are identifying the molecular mechanisms by which lncRNA mediates both structural and functional roles. LncRNA can regulate gene expression at both transcriptional and post-transcriptional levels, including splicing and regulating mRNA processing, transport, and translation. Much current research is aimed at elucidating the function of lncRNAs in breast cancer and mammary gland development, and at identifying the cellular processes influenced by lncRNAs. In this paper we review current knowledge of lncRNAs contributing to these processes and present lncRNA as a new paradigm in breast cancer development.

Keywords: breast cancer; epigenetics; gene regulation; long non-coding RNA; mammary gland development.

FIGURE 1

Schematic showing genomic organization of different lncRNAs. The DNA strands are shown in black and gray lines. The black and white boxes represent exons of protein coding and lncRNA genes, respectively. LncRNAs are classified as sense (e.g., Intronic or overlapping) or antisense, reflecting the way they overlap with protein coding genes in the same or opposite direction, respectively. The diagram shows that lncRNAs can be antisense to protein coding (antisense lncRNA) or originate from introns of protein coding genes either as by-products of mRNA or as independent transcripts (intronic lncRNA, sense lncRNA). LncRNA also can be transcribed from intergenic regions of the genome (lincRNA). LncRNA genes can overlap the protein-coding genes (overlapping transcript).

FIGURE 2

Schematic illustrating the functions of lncRNAs. (A) LncRNAs (e.g., HOTAIR) can suppress transcription by interacting with PRC1 and PRC2 complexes as well as with other chromatin modifying proteins, maintaining heterochromatin status and suppressing transcription (reviewed in Gibb et al., 2011; upper panel). Trithorax complexes also can interact with lncRNA (e.g., HOTTIP) and induce transcription (lower panel; reviewed in Jobe et al., 2012). (B) LncRNAs are proposed to be transcribed at enhancer regions and can function in the establishment and maintenance of enhancer–promoter looping and activation of gene expression (Orom and Shiekhattar, 2013). (C) LncRNAs such as MALAT1 can regulate alternative splicing by interacting with the spliceosomal machinery (Tripathi et al., 2013). (D) Specific lncRNAs are transcribed and bind to and titrate away protein factors. Decoy lncRNAs can bind to protein factors such as transcription factors and chromatin modifiers. This leads to broad changes in transcriptomes. (E) Intronic regions of many lncRNAs host snoRNAs. The snoRNAs derived from these lncRNAs remain in the nucleus while the spliced transcript can move to the cytoplasm and bind either to polysomes or to other proteins (Smith and Steitz, 1998). (F) LncRNAs can bind to miRNAs to sequester them and inactivate their repressive functions (reviewed in Gibb et al., 2011). (G) Many lncRNAs are associated with polysomes (van Heesch et al., 2014), while the mechanisms of many are yet to be identified, antisense lncRNAs such as UCHL1AS regulate the translation of associated mRNAs. (H) Decoy lncRNAs such as GAS5 are present in both in the cytoplasm and the nucleus: GAS5 translocates from the cytoplasm into the nucleus with glucocorticoid receptor in response to dexamethasone (Kino et al., 2010). TF, transcription factor; RP, RNA polymerase; E1, exon1.

FIGURE 3

List of lncRNAs reported in this review based on their localization, function, and expression pattern. The function of each lncRNA is above each box. The red and black represent the genes upregulated and downregulated respectively in breast cancer.