Abstract
Non-coding RNAs (ncRNAs) play major roles in development and cancer progression. To identify novel ncRNAs that may identify key pathways in breast cancer development, we performed high-throughput transcript profiling of tumor and normal matched-pair tissue samples. Initial transcriptome profiling using high-density genome-wide tiling arrays revealed changes in over 200 novel candidate genomic regions that map to intronic regions. Sixteen genomic loci were identified that map to the long introns of five key protein-coding genes, CRIM1, EPAS1, ZEB2, RBMS1, and RFX2. Consistent with the known role of the tumor suppressor ZEB2 in the cancer-associated epithelial to mesenchymal transition (EMT), in situ hybridization reveals that the intronic regions deriving from ZEB2 as well as those from RFX2 and EPAS1 are down-regulated in cells of epithelial morphology, suggesting that these regions may be important for maintaining normal epithelial cell morphology. Paired-end deep sequencing analysis reveals a large number of distinct genomic clusters with no coding potential within the introns of these genes. These novel transcripts are only transcribed from the coding strand. A comprehensive search for breast cancer associated genes reveals enrichment for transcribed intronic regions from these loci, pointing to an underappreciated role of introns or mechanisms relating to their biology in EMT and breast cancer.
Highlights
Advances in gene expression profiling using technologies such as whole genome tiling arrays (GTAs) and deep-sequencing (“next-gen”) within the last decade have resulted in the unexpected realization that ~90% of the human genome is transcribed [1, 2]
GTA analysis reveal intronic regions associated with breast cancer To identify novel genes that are important to breast cancer, total RNA samples (S1 File) were purchased from Ambion and Asterand plc and used to generate disease versus control cDNA samples
Genetic markers that can help in the diagnosis, prognosis, or treatment of breast cancer are highly desired to improve both breast cancer treatment and understanding of the underlying biology
Summary
Advances in gene expression profiling using technologies such as whole genome tiling arrays (GTAs) and deep-sequencing (“next-gen”) within the last decade have resulted in the unexpected realization that ~90% of the human genome is transcribed [1, 2]. While many important classes of non-protein coding RNAs (ncRNAs) have been identified, ranging from small RNAs. PLOS ONE | DOI:10.1371/journal.pone.0120296. Novel Breast Cancer-Associated Intronic Sense RNAs such as microRNAs (miRNAs) to long noncoding RNAs (lncRNAs) [3], to extraordinarily long ncRNAs such as the 108 kb Air transcript [4], the functions of most ncRNAs remain unknown [5]. One approach to discover important RNAs is to identify those that are dysregulated in diseases. Transcriptome sequencing in cancer tissues has led to the discovery of novel ncRNAs such as PCAT-1, a specific regulator of cell proliferation [7] and chimeric, cancer-associated RNAs [8]
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