Increased expression and copy number amplification of LINE-1 and SINE B1 retrotransposable elements in murine mammary carcinoma progression

Alberto Gualtieri,Annalucia Serafino,Corrado Spadafora,Ilaria Sciamanna,Federica Andreola,Paola Sinibaldi-Vallebona

doi:10.18632/oncotarget.1188

Abstract

In higher eukaryotic genomes, Long Interspersed Nuclear Element 1 (LINE-1) retrotransposons and endogenous retroviruses represent large families of repeated elements encoding reverse transcriptase (RT) proteins. Short Interspersed Nuclear Element B1 (SINE B1) retrotrasposons do not encode RT, but use LINE-1-derived RT for their retrotransposition. We previously showed that many cancer types have an abundant endogenous RT activity. Inhibition of that activity, by either RNA interference-dependent silencing of active LINE-1 elements or by RT inhibitory drugs, reduced proliferation and promoted differentiation in cancer cells, indicating that LINE-1-encoded RT is required for tumor progression. Using MMTV-PyVT transgenic mice as a well-defined model of breast cancer progression, we now report that both LINE-1 and SINE B1 retrotransposons are up-regulated at a very early stage of tumorigenesis; LINE-1-encoded RT product and enzymatic activity were detected in tumor tissues as early as stage 1, preceding the widespread appearance of histological alterations and specific cancer markers, and further increased in later progression stages, while neither was present in non-pathological breast tissues. Importantly, both LINE-1 and SINE B1 retrotransposon families undergo copy number amplification during tumor progression. These findings therefore indicate that RT activity is distinctive of breast cancer cells and that, furthermore, LINE-1 and SINE B1 undergo copy number amplification during cancer progression.

Highlights

A strikingly unexpected finding emerging after the completion of the human genome sequencing indicates that protein-coding genes make up a mere 1.2% of the human genome, while the rest of the genomic DNA is devoid of protein-coding functions [1]
As a follow up on the empirical evidence that LINE1-encoded reverse transcriptase (RT) is implicated in tumorigenesis, it was of interest to assess Long Interspersed Nuclear Element 1 (LINE-1) retrotransposon expression during breast cancer progression
These results suggest that a reverse transcription-mediated www.impactjournals.com/oncotarget amplification process is triggered at cancer onset for both LINE-1 and Short Interspersed Nuclear Element B1 (SINE B1) retrotransposon families and continues throughout tumor progression

Summary

Introduction

A strikingly unexpected finding emerging after the completion of the human genome sequencing indicates that protein-coding genes make up a mere 1.2% of the human genome, while the rest of the genomic DNA is devoid of protein-coding functions [1]. A wealth of studies have disclosed global regulatory roles for ncRNAs [11,12], small RNA families [13], ultra conserved regions (UCRs) [14,15] and retrotransposable elements (retroelements, [16,17]). The latter account for about 45% of the human genome [1, 18] and can be subdivided into two large families, i.e. long terminal repeat (LTR)-containing endogenous retroviruses www.impactjournals.com/oncotarget

Methods

Results

Conclusion