Fifteen years ago, the Steroid receptor RNA activator (SRA) was identified as a functional non-coding RNA able to increase the activity of the estrogen receptor (ER), a critical player mediating the mitogenic role of estradiol in breast cancer. Interestingly, four years later, SRA appeared to be the first ever discovered functional RNA also able to encode a protein (SRAP). As such, the products of the SRA1 gene delineate a fascinating bi-faceted system involving both a functional RNA and a protein. Since its discovery, the non-coding aspect of this system has been widely investigated, with multiple groups gathering information on SRA structure and related functions. Overall, the non-coding SRA transcript is thought to act as a broad co-regulator modulating the activity of different transcription factors. Conversely, limited information has been obtained on the coding aspect (SRAP) of this system，even though SRA/SRAP is currently believed as a whole to be involved in several mechanisms including tumourigenesis, tumour progression, myogenesis and adipogenesis.
In this body of work, I have attempted to define the clinical relevance of SRAP to breast cancer and extend the understanding of the cellular processes potentially regulated by this protein. I have first established that SRAP had the potential to become a new prognostic and predictive factor in specific groups of patients. Indeed, I have demonstrated, using tissue microarray analyses (TMAs), that SRAP expression was up-regulated in some breast tumours, with high levels associated with poor prognosis in Estrogen Receptor (ER) positive breast cancer patients. Using the same technique, I have further identified a positive association between a positive response to tamoxifen treatment and a high level of SRAP expression in a large cohort of ER-α negative cases. This highlights the potential for SRAP to become a new predictive factor of response to endocrine therapy in this specific group of patients. Using RNA-seq to define the transcriptomes of cervical Hela and breast MDA-MB-231 cancer cells upon depletion or overexpression of this protein, I further identified cellular movement amongst the potential cellular processes affected by changes in SRAP expression. Using classical trans-wells assays as well as an live-cell imaging assays, I have confirmed that SRAP indeed regulates individual cancer cell motility.
Overall, my results provide critical new insights into the potential functions of the protein counterpart of the intriguing SRA/SRAP bi-faceted gene system. SRAP herein appears as a potential new therapeutic target in the fight against breast cancer that remains to be further investigated. / February 2017
| Identifer | oai:union.ndltd.org:MANITOBA/oai:mspace.lib.umanitoba.ca:1993/32000 |
| Date | 11 1900 |
| Creators | Yan, Yi |
| Contributors | Leygue, Etienne (Biochemistry and Medical Genetics), Murphy, Leigh (Biochemistry and Medical Genetics) Myal, Yvonne (Pathology) Xie, Jiuyong (Physiology and Pathophysiology) Rennie, Paul (University of British Columbia) |
| Publisher | Breast cancer research, Journal of cancer research and clinical oncology, annals of oncology, Febs letter |
| Source Sets | University of Manitoba Canada |
| Detected Language | English |
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