Nucleic Acids Research Advance Access originally published online on May 29, 2009
Nucleic Acids Research 2009 37(13):4518-4531; doi:10.1093/nar/gkp441
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Nucleic Acids Research, 2009, Vol. 37, No. 13 4518-4531
© 2009 The Author(s)
This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/2.0/uk/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
Molecular Biology |
Increasing the relative expression of endogenous non-coding Steroid Receptor RNA Activator (SRA) in human breast cancer cells using modified oligonucleotides
1Department of Biochemistry & Medical Genetics, 2Manitoba Institute of Cell Biology (MICB) and 3Department of Pathology, University of Manitoba, 770 Bannatyne Avenue, Winnipeg, Manitoba, R3E0W3, Canada
*To whom correspondence should be addressed. Tel: +1 204 977 5608; Fax: +1 204 789 3900; Email: eleygue{at}cc.umanitoba.ca
Received March 10, 2009. Revised May 8, 2009. Accepted May 11, 2009.
Products of the Steroid Receptor RNA Activator gene (SRA1) have the unusual property to modulate the activity of steroid receptors and other transcription factors both at the RNA (SRA) and the protein (SRAP) level. Balance between these two genetically linked entities is controlled by alternative splicing of intron-1, whose retention alters SRAP reading frame. We have previously found that both fully-spliced SRAP-coding and intron-1-containing non-coding SRA RNAs co-exist in breast cancer cell lines. Herein, we report a significant (Student's t-test, P < 0.003) higher SRA–intron-1 relative expression in breast tumors with higher progesterone receptor contents. Using an antisense oligoribonucleotide, we have successfully reprogrammed endogenous SRA splicing and increased SRA RNA–intron-1 relative level in T5 breast cancer cells. This increase is paralleled by significant changes in the expression of genes such as plasminogen urokinase activator and estrogen receptor beta. Estrogen regulation of other genes, including the anti-metastatic NME1 gene, is also altered. Overall, our results suggest that the balance coding/non-coding SRA transcripts not only characterizes particular tumor phenotypes but might also, through regulating the expression of specific genes, be involved in breast tumorigenesis and tumor progression.