Ribosomal RNA Transcription Regulation in Breast Cancer

Abstract

Ribosome biogenesis is a complex process that is responsible for the formation of ribosomes and ultimately global protein synthesis. The first step in this process is the synthesis of the ribosomal RNA in the nucleolus, transcribed by RNA Polymerase I. Historically, abnormal nucleolar structure is indicative of poor cancer prognoses. In recent years, it has been shown that ribosome biogenesis, and rDNA transcription in particular, is dysregulated in cancer cells. Coupled with advancements in screening technology that allowed for the discovery of novel drugs targeting RNA Polymerase I, this transcriptional machinery is an increasingly viable target for cancer therapies. In this review, we discuss ribosome biogenesis in breast cancer and the different cellular pathways involved. Moreover, we discuss current therapeutics that have been found to affect rDNA transcription and more novel drugs that target rDNA transcription machinery as a promising avenue for breast cancer treatment.

Keywords: RNA Polymerase I; breast cancer; nucleolus; rRNA synthesis; ribosome biogenesis.

Figure 1

Morphometric alteration of nucleoli in histological sections from two BC samples. Nucleolar proteins are silver stained to visualize nucleoli (black color). Nucleoli in sample (A), with wild type p53 and hypo-phosphorylated pRb, showed small size of nucleoli with heterogeneous number per cell. Sample (B) was characterized by mutated p53 and deleted RB, having a higher proportion of enlarged nucleoli. Bar = 10 μm. Reproduced with permission from “Ribosome biogenesis and cancer” [9].

Figure 2

Complex regulation of RNA polymerase I transcription in breast cancer. Hyperactivation of upstream signaling pathways PI3K/AKT/mTOR, Wnt/beta-catenin, and c-Myc converge on and upregulate RNAPI transcription activity. In contrast, non-canonical Wnt signaling via Wnt5a and tumor suppressor proteins p53, pRB, pTEN, and pARF downregulate rDNA transcription. Additionally, ncRNAs miR-424-5p and SLERT can regulate this process. Attenuation of tumor suppressors by inactivation frequently results in elevated rRNA synthesis, and thus increased ribosome production to sustain aberrant proliferation in breast cancer. Ribosome biogenesis (on right) begins with the transcription of the rDNA by RNAPI that yields the 47S pre-rRNA transcript. The transcript is subsequently processed and assembled with ribosomal proteins and the mature 5S rRNA to form the pre-40S and pre-60S subunits. These subunits combine in the cytoplasm to perform protein synthesis.

Figure 3

Antineoplastic agents and their RNAPI machinery targets. This schematic represents the first step in ribosome biogenesis, rDNA transcription, and the drugs found to affect this process. Denoted in blue are “older” drugs already in use for cancer treatments and denoted in red are the newly discovered drugs that have been in recent clinical trials, with the exception of the BMH and P1-B1 molecules. The red star highlights direct interaction with the rDNA.